Uses of SAR-derived information to support various components and actions of seismic risk management
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"688",leadTitle:null,fullTitle:"Genetics and Pathophysiology of Essential Hypertension",title:"Genetics and Pathophysiology of Essential Hypertension",subtitle:null,reviewType:"peer-reviewed",abstract:"This book, authored by renowned researchers in the field of Hypertension Research, details the state of the art knowledge in genetics, genomics and pathophysiology of Essential hypertension, specifically the genetic determinants of hypertension and role of gene variants in response to anti-hypertensive therapy. 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One of the scientific disciplines in which SAR data have generated a real breakthrough is Solid Earth Geophysics. As soon as the first differential SAR interferograms appeared on scientific journals, describing the surface crustal changes due to earthquakes or inflation of volcanic edifices, geophysicists realized that their science was to greatly benefit from these new data.
The reasons were clear: before the InSAR era crustal deformation was measured using very time-consuming, ground based methods, as leveling, triangulation, trilateration; all requiring costly networks and measurement campaigns. The same was true for the GPS technique, appeared only few years before. SAR interferometry made things simpler and cheaper, although with some limitations; probably the most appealing features of InSAR deformation measurements were their spatial imaging capacities and the high ground resolution. These allowed an unprecedented way to look at all the natural phenomena causing, or derived from, surface deformation.
In this chapter we start describing technical aspects related to the way InSAR data are exploited to derive the parameters of the sources of an observed phenomenon, focusing the attention on the seismic and volcanic activity. We present the state-of-the-art techniques to this inference problem, describing the most common inversion algorithms and analytical models, especially those implemented for the description of the seismic and volcanic cycles. Other technical aspects, as the role played by the data uncertainty, the existing strategies to reduce the data redundancy and the way sources of different nature interact with each other, are also presented to provide useful basics for the reader interested InSAR data modeling.
The second part of this chapter focuses on the practical use of InSAR data and derived models, describing their assimilation in the seismic risk assessment and prevention or during the disaster response. Examples of already existing operational procedures, research and development pilot projects, current and future SAR missions, including Sentinel-1, are also presented to complete this detailed overview on the role played by SAR and SAR-derived information in Solid Earth Geophysics.
InSAR modeling is an inference process used to define the properties of a realistic geophysical source, or combination of sources, from a set of geodetic measurements. First aspect to clarify is the definition of “realistic”, strongly related to
Accepting a simple approximations, as a free surface without topography overlying an homogeneous and isotropic half-space, ordinary geophysical models can be expressed as a set of equations in explicit form, where the modeled surface displacement
being
Though the above approximations might appear excessive, in most cases they provide very good description of the sources, a fact that is indeed reflected in their massive use in Geophysics. Commonly used sources in the literature are:
Parameters required by the Okada model.
The Mogi equations can be indifferently written in terms of pressure change or volume change; however, the volume/pressure conversion requires the definition of a virtual source radius.
Parameters required by the Mogi model
Several other sources have been proposed in the literature, with the aim of providing more realistic solutions to describe geophysical phenomena: dislocation over a finite triangular source [8]; volume variation of a dipping finite prolate spheroid [9]; inflation of an arbitrarily oriented triaxial ellipsoidal cavity [10]; pressure change in a penny-crack source [11]; closed vertical pipe [12]; stress induced by a finite spherical source [13]. A description of the differences among all these sources is beyond the scope of this article, and we refer the reader to the cited literature.
Lastly, we remark the existence of semi-analytical solutions for a layered crust [14] [15], even with a visco-elastic rheology [16]; however they often require a considerable computational time, preventing their use in non-linear inversion schemes, where thousands of forward calculations are often needed. The same limitation affects finite-element models, unless used to build the Green’s function matrix as explained in the next section.
For almost all the listed models, the geometric parameters (position, depth, dimension, orientation, etc…) are non-linearly related to the surface displacement. On the contrary, “intensity” parameters, as the dislocation for the Okada model or the pressure change for a Mogi model, have a linear dependency with the surface displacement. The retrieval of non-linear and linear parameters from geodetic data follows different inversion strategies, explained in the next section.
A further Okada-derived model, widely used to model earthquakes, consists of an array of single Okada sources, or
Okada-based, compound source for slip or opening distributed models
InSAR measurements are relative, therefore the displacement maps are often related to a reference point considered stable or with a known deformation. This point sometimes turns out to be inappropriate: it could fall in an area affected by atmospheric artifacts; the non-zero displacement field could be larger than the image frame; the GPS value used to tie the reference point might contain a very long wavelength tectonic signal. Furthermore, orbital inaccuracies might introduce artificial linear ramps or even quadratic surfaces. Thus a further non-geophysical source must be often considered, to account for possible improper reference points and/or possible orbital artifacts.
This model can be implemented as a second order surface of the type
so that the apparent displacement
We remark that all the geophysical and orbital sources We adopt the misleading definition “orbital source” only because it is mathematically handled just like the Okada or Mogi equations.
Current approaches to the modeling of geodetic data are the evolution of pioneer studies where the amount of geodetic measurements where certainly lower than nowadays [17][18][19] and the availability of geophysical models were still limited: solutions for dislocation in an elastic medium were available only for some simple fault configurations and for point sources [20][21]. However, non-linear and linear inversion strategies were essentially the same presently adopted. What deeply changed through the decades is the amount of observed data, with InSAR playing a lead role.
An inversion algorithm is a procedure to infer some source parameters so that the modeled, or predicted, surface displacement best reproduces the observed one. We must firstly provide a definition for “best fit”; almost every model shown in literature assumes that the best parameter estimate (
This choice implies that
The inversion strategy must be chosen according to the source parameters
Any non-linear inversion scheme is based on the realization of a sequence of forward calculations as in (1) until the condition (3) is satisfied or, in other terms, a set of rules to iteratively change the
A typical issue to face in a non-linear inversion is the presence of an unpredictable number of local minima, corresponding to unsatisfactory solutions; a robust algorithm should be able to take a cost function out from local minima. Unfortunately, only few strategies guarantee the achievement of this goal, for instance Simulated Annealing [24]; however, they are incompatible with a reasonable processing time Simulated Annealing is largely used in non-linear inversions due to the ease of its implementation, but never with the cooling schedule that guarantees to find the global minimum, that would require a nearly endless computation time.
In our experience, the Gauss-Newton or gradient descent methods, as the Levemberg-Marquardt algorithm which is a mix of both [25], provide excellent results with a short processing time; although this algorithm does not consider any stratagem to escape from local minima, its implementation with multiple restarts provides an efficient strategy to identify the global minimum.
We incidentally remark that the repeated calculation of forward models makes unfeasible the use of finite element models in any inversion scheme, because of the long time needed to setup and calculate even a single forward model.
A different approach is adopted when all the parameters to invert are linearly related to the surface displacement, as occurs with the strike-slip, dip-slip and opening components for an Okada model, with the volume variation in a Mogi source or with the coefficients of equation (2). In this case, the inversion can be set up in a matrix form of the type:
where the vector collecting all the parameters
It is worth noting that the number of unknowns
being
However, if we consider the practical problem of finding the coseismic slip distribution as in Figure 6e, solutions found via (4) and (5) are generally not acceptable because of the weak control that InSAR surface measurements have on deep parameters, leading to highly scattered
where the Green’s functions
Other inequality constraints, such as the positivity (Non-Negative Least Square), can be introduced as well, to further increase the solution reliability; in the modeling of a coseismic displacement field, the constraint
Unlike non-linear inversion, in linear inversions the use of finite elements models (FEM) is not prohibitive in terms of computational time. In this stage, the heavy forward calculation must be done only once to build the kernel matrix
Based on the elastic rebound theory formulated by Harry Fielding Reid in 1910, after the 1906 San Francisco earthquake, a seismic cycle is formed by a slow accumulation of stress and deformation, as consequence of the forces acting from the underlying Earth mantle, followed by an impulsive release of stress and energy when the internal strength is exceeded such that the brittle crust breaks (Figure 4). These two phases, which we refer to as inter- and co-seismic, are completed by a post-seismic phase, where different phenomena may induce further deformations during a short- to mid-term period after the earthquake (Figure 5).
Simplified description of the elastic rebound theory: black arrows describe the steady interseismic forces acting on a locked fault until its sudden failure.
The co-, post- and inter-seismic phases have completely different characteristics in terms of duration and crust behavior. During the inter-seismic phase, faults are locked on the upper crust and the underlying forces act to deform the surface with relatively constant rates of few millimeters per year over large areas. As soon as the accumulated stress exceeds the locking frictional forces, the crust cracks and part of the deformation around the faulted area is elastically and permanently recovered in few seconds. Soon after the earthquake, for a period lasting from few minutes to some years, a further deformation occurs as a consequence of the sudden co-seismic stress release. Deformation rates roughly follow a decreasing exponential law (Figure 5) and can be explained in terms of one or a combination of the following factors: residual dislocation on the ruptured fault (after-slip models), viscoelastic relaxation of the lower crust driven by the coseismic stress change, poro-elastic rebound due to the migration of fluids in the crust ([28] and references therein).
CGPS data related to the 2009 L’Aquila earthquake, showing the steady tectonic drift, the sudden coseismic displacement and the exponential post-seismic relaxation (by courtesy of Roberto Devoti, INGV)
This basic description allows to state how SAR derived data can play a crucial role in the understanding of a seismic cycle. In the co-seismic phase, the expected surface displacement, from tens of centimeters to several meters, and the nearly perfect elastic behavior due to the instantaneous deformation are perfect conditions to model the standard two-pass interferometry with the Okada solutions. [30][31][32] showed that since the 1992 Landers earthquake, the onshore deformation for all the significant earthquakes worldwide (M > 5.5) have been imaged with the standard InSAR interferometry and most of them have been modeled with the Okada model. A common problem found in this approach is that, in general, coseismic interferograms contain a contribution from the post-seismic deformation that can affect some fault parameters [31]. Isolating the co-seismic signal may not be straightforward, but the introduction of continuous measurements, such as CGPS, may be helpful in the post-seismic contribution removal.
During the inter-seismic phase, steady deformation rates are often assumed; however, expected values are of the order of some millimeters per year, so they can be hardly detected with two-pass interferometry: the time needed to accumulate a signal above ordinary InSAR artifacts would be too long to preserve the phase coherence; for this reason, time-series techniques like PS [33], SBAS [34], or image stacking are indicated to get mean velocity maps with millimetric accuracy [35], provided that a consistent number of images is available [36][37]. Elastic models have also been used to fit inter-seismic data [38][39][40], however its use must be carefully considered because the assumption of elasticity can lack of realism.
Another important aspect is the apparent similarity between long-wavelength tectonic signals spreading through a whole SAR image frame and the orbital artifacts [41]. In this context, the use of GPS, unaffected by such artifacts, to constrain the velocity maps can be very effective [36][41].
Post-seismic relaxation has intensity and duration strongly dependent on the earthquake magnitude; short intervals can be easily encompassed between two SAR acquisition [42][43], often cumulated with the co-seismic effects. In this case the two contributions cannot be distinguished unless external continuous observations, as GPS, are introduced [44]. For large earthquakes, the post-seismic effects can last from months to years, and the InSAR time-series approach can be effectively used to describe the crustal displacement time evolution [28]. While the observed displacement is interpreted in terms of after-slip over the seismogenic fault, the Okada solutions can be used to model the signal [45]. However, for long-term deformation, visco-elastic models should be used [42].
Regardless from the seismic cycle phase, deformation modeling with the Okada solution is generally subdivided into two steps: a first non-linear inversion to retrieve all the unconstrained source parameters, followed by a linear inversion to get the distribution of the dislocation over the fault(s). The only measure to adopt before running the linear inversion is the widening of the fault plane obtained via non-linear inversion: the latter represents only a mean source with a mean dislocation value, therefore the fault plane must be enlarged to let the slip vanish to zero.
While most of the signal is already reproduced with uniform slip sources, high frequency spatial fluctuations are recovered adopting the Okada-derived distributed slip sources (Figure 6), solved with the linear system (4).
Coseismic displacement field, for the 2003 Bam (Iran) earthquake, retrieved with InSAR (a), modeled with a uniform slip Okada source (b) and with a distributed slip, Okada source (c). Models for (b) and (c) are shown in (d) and (e), respectively.
A last remark is about the possibility of obtaining a more realistic source by relaxing the condition of a flat half-space. The possibility of accounting for the topography in the overall system setup will be described in the next section, where this aspect plays an important role.
The volcanic activity monitoring is conditioned by our ability to describe and understand the eruption cycle. Several steps can be identified in this cycle: magma generation, melting, storage and ascent, crustal assimilation, degassing, crystallization and surface eruption, not all of which can necessarily occur. In any case, evidences of the incoming eruption can be noticed only late in the cycle and InSAR data are crucial to provide information for the hazard mitigation, even for not erupting stages [46].
In the case of volcanic phenomena, several factors contribute to make the assumption of elasticity less reliable than the co-seismic case; magma intrusion starts below the seismogenic crust, thus involving ductile, high temperature layers able to deform aseismically. Furthermore, inflating and deflating phenomena involve times long enough to activate a visco-elastic behavior. Lastly, the half-space approximation is debatable as well, because of the inevitable significant topography of the investigated areas. Despite this limitations, the aforementioned elastic models have been largely applied in volcanology, with the aim of reproducing almost all surface deformations detected with InSAR [47][3][48][4][49][50].
Magma chamber inflation or deflation is generally modeled with the simple Mogi source, due to the ease of its implementation compared with its effectiveness [47][51]. For magma intrusion in vertical (dykes) or horizontal (sills) cracks, distributed opening sources based on the Okada model are instead adopted [48][50].
Sometimes, complex patterns revealed by InSAR suggest the implementation of a multiple-source system, where also seismic sources can have a role, as shown by the 2005 Afar dyking phase described in [52] (Figure 7). In such contexts, the double step non-linear/linear inversions is adopted to first constrain the source geometries, then to retrieve the slip and opening distributions.
The complex system of sources (magma chambers, dykes and faults) used to model the Afar dyking phase (from [
For the long-term crustal deformation, time-series techniques have shown their effectiveness to describe the surface change, even when repeated inflation-deflation cycles are present [53]. In this case, modeling can be carried out by fixing the non-linear source parameters and then fitting the time dependent signal by only varying the linear parameter, i.e. the volume or pressure change.
A further remark, in this context, is about the important role played by topography, since strong elevation variations are expected in the investigated areas; for Mt. Etna, for instance, total relief difference is over 3000 m. To mitigate the assumption of flat half-space, topographic corrections can be applied to the analytical models. This correction consists in the calculation of the source depth not from the zero level of the free surface, but adding the real elevation of the point for which the predicted displacement is being calculated. Such compensation has been compared with finite element models, providing a satisfactory improvement on the modeled data [54][55], as shown in Figure 8.
Comparison between displacement profiles from analytical and numerical models, with and without topographic corrections (from [
Finally, the frequent presence of stratified atmosphere, altering the interferogram with fringes due to topography-related radar delays, can be discriminated by comparing independent interferograms, assuming weather conditions uncorrelated in time.
Since displacement maps derived from InSAR processing may contain millions of valid pixels, with an high degree of spatial correlation, a way to reduce the data must be adopted in any inversion strategy. Several criteria have been proposed in literature, among which we recall here three different approaches: Quadtree decomposition [56][57], resolution-based [69] and regular mesh [58][59].
A general rule to state which is the best method does not exist, though the Quadtree algorithm is the most used. It is a decomposition algorithm aimed at preserving the “amount of information” in the image, and is in general based on the spatial gradient of the signal; it follows that areas with higher displacement values are sampled at higher spatial frequencies (Figure 9b).
The resolution-based algorithm proposed by [69] is driven by an already known source; this allows to calculate the data resolution matrix [22] used to define where surface data must be sampled to constrain the linear source parameters.
Finally, regular sampling is also widely adopted, since its ease of implementation and its effectiveness in imposing a sampling density independent from displacement values. In fact, the InSAR data resolving power, i.e. the maximum detail level achievable on a source, strongly depends on the location of the observed points, as shown in [60] and not on the displacement field itself. The sampling can be manually customized by defining areas with different sampling density; this also allows to have a good control on the number of observed data to handle in the inversion (Figure 9b).
The 2003 Bam (Iran) earthquake displacement field (a), downsampled with the Quadtree algorithm (b) and a regular mesh with variable posting areas (c).
InSAR measurements are always affected by different sources of uncertainty, as shown by the ample literature on this topic (see [23] and references therein). Here we discuss the strategies generally adopted to propagate the data uncertainty to the source parameters in the non-linear and linear inversions.
For convenience, linear inversion is firstly analyzed, where ordinary rules for the error propagation can be applied, as:
where the full variance/covariance matrix
where C0 is the covariance at zero distance, generally lower than the overall
Empirical covariance function (from [
The full variance/covariance matrix
In the non-linear case, a formal expression of the uncertainty propagation is difficult to obtain and an empirical approach is commonly used: for tens or hundreds of times synthetic noise datasets
The
to get the synthetic noise dataset
Uncertainty (red histograms) and trade-offs between parameters (from [
Models derived from InSAR data give important hints for the hazard assessment, as discussed later in this chapter, and in this respect an increasingly considered aspect is the way sources interact with each other. An earthquake occurs when the internal strength is exceeded by the surrounding stress, loaded during the interseismic phase. We generally do not know the absolute stress value for a given crust volume, primarily because the loading phase spans through centuries or millennia. On the contrary, we can quantitatively calculate the stress variation induced by a fault dislocation.
The stress released during a seismic event perturbs an area extending far from the source itself, where surrounding locked faults are likely to be present. The rearranged stress conditions following an earthquake may increase or decrease the current (unknown) shear stress level acting on a fault surface: we can therefore calculate if such a variation moved the receiver source closer to its failure.
The analytical solutions proposed in [63] allow to calculate the internal deformations induced by a dislocation over a fault plane; internal deformation can be then easily converted into stress variations, using the Coulomb Failure Function variation (ΔCFF), described in [64], and defined as
\n\t\t\twhere Δτ is the shear stress change over the fault, calculated for a given slip direction,
Despite its apparent simplicity, the application of the stress change analysis must be considered with care, because of the intrinsic unknown of the already existing background stress, the mislocation of possible receiver sources, the uncertainty of the triggering source parameters (derived from inversion) and the presence of spatial inhomogeneities. They all introduce a high level of uncertainty, as discussed in [66] and references therein.
The stress variation analysis has been successfully adopted also in a volcanic context, to study the interaction among sources of different nature: magma chambers, dykes, faults [67][68][50]. Though these analyses are always conducted
However the warning issued by [64] is still holding: “much work remains before we can understand the complete story of how earthquakes work”. The CFF analysis is a powerful tool to describe the interaction between sources, but it is still not adequate to deterministically state how close to the failure a receiver source has been pushed by any triggering event.
The use of SAR data and techniques has greatly stimulated the progress of the Solid Earth science. Globally, over three hundreds deformation fields related to the earthquake cycle (including inter-, co-, and post-seismic deformation), and over a thousand volcanic edifices, have been studied using SAR data since the beginning of the “InSAR era” [30] [31] [32][70][71]. Important new knowledge has been acquired on processes such as fault dislocation, fault segmentation, magma and gas migration, volcanic spreading, stress transfer, strain accumulation and release, poro-elastic diffusion, and visco-elastic relaxation. Better descriptions of the seismic and volcanic cycles are today available thanks to these studies.
Soon after InSAR started to demonstrate its potential to sustain new scientific developments in crustal deformation studies, practitioners started to investigate the possible use of this new information in the risk management activities [72][73]. It was rapidly realized that the new geodetic "imaging" capabilities provided by satellite SAR sensors could strongly support two main components of the disaster risk management, namely the assessment/prevention and the response components.
However, the space and ground segments of the first satellite SAR systems (i.e. ERS, ENVISAT, JERS, ALOS) were targeted mainly to scientific use and, while they could provide delayed data to carry out pre- or post-disaster scientific analyses eventually supporting the hazard assessment component [74], they lacked the near real time capabilities needed for use in the response phase. Even after the launch of the first commercial SAR satellite in 1995 (Radarsat-1) the use of SAR data in disaster risk management did not flourish, due to the lack of a constant repeat pass, global coverage, and to the high costs required to maintain updated archives.
This situation will change radically in 2014, when the European Space Agency Sentinel-1 operational satellite (and its companion Sentinel-1 B in 2015) will start to provide a full InSAR coverage of nearly all land areas with pre-defined, constant repeat pass [75]. The Sentinel-1 data will be delivered in near real time to selected service providers to generate support products during natural disasters or emergencies. Sentinel-1 minimum revisit time will be 12 days, improving to 6 days after the launch of the second satellite, and the mission continuity will be guaranteed for many years [76].
While the "flat" data flow rate and the "full and open data access" policy of the Sentinels will certainly represent a breakthrough for the use of remote sensing data for operational risk management, other SAR satellite constellations have already started to demonstrate the potential for operational emergency response. The Italian Space Agency COSMO-SkyMed four-satellite constellation was in fact expressly developed to support the monitoring and assessment of natural and anthropogenic disasters [77], although it is a dual-use mission, also employed for defense purposes. This constellation presently allows much shorter revisit times than possible with Sentinel-1, down to 1 day depending on satellite.
In the following sections, with reference to Table 1, we will show examples and examine the operational capabilities of InSAR data, and of geophysical models they can constrain, to support activities in the two main components of seismic risk management: the risk assessment/prevention, and the response to a seismic crisis.
Seismic Hazard Assessment (SHA) is the process of calculating, for a given area, the probability of the occurrence of a certain ground shaking level within a defined period of time. The typical SHA synthetic result for a region is a map showing the spatial variations of the horizontal Peak Ground Acceleration which have a probability of exceedance of 10% within a 50 or 75 year time frame. These maps (complemented by more detailed, site-specific seismic hazard curves) are generated using information on the existing seismic sources, their activity rates and maximum earthquake magnitude, and by estimating the relations between epicentral distance and ground motion for a given earthquake magnitude and fault type (attenuation relations).
InSAR data can provide important information regarding the earthquake source (Table 1). One field of analysis deals with the actual detection of faults by means of their geomorphological signature (e.g. linear scarps, triangular facets on mountain fronts, displaced terraces, drainage network offsets, etc.). This is a classical application of photo-interpretation techniques (structural and geomorphic), in which B&W SAR intensity images give a contribution comparable to optical images. The satellite image analysis can provide especially valuable support to the mapping of active faults and earthquake sources, in areas which are of difficult access and for which detailed geological data do not exist.
While intensity image analysis reveals the fault presence by investigating peculiar landforms created by surface deformation cumulated during geological times, multitemporal InSAR processing can provide a quantitative measurement of the ongoing deformation rates (and their spatial patterns) used to characterize the fault behavior. Many scientific results obtained in the last ten years [32] have contributed precious information for the parameterization of the seismic sources [79][80][81][82][83][84], but also for the definition of the present deformation rates in areas where multiple sources are present [37][85] [86][87][88][89], for the partitioning of strain among different faults [90][91], for the improvement of tectonic models in seismogenic areas [92][93][94].
\n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|
\n\t\t\t\t | \n\t\t\tSeismic hazard | \n\t\t\tIdentification of active faults. | \n\t\t\tStructural maps. | \n\t\t\tAmplitude image analysis. | \n\t\t
Parameterization of activity rates. | \n\t\t\tLong-term ground displacement rates maps (inter-seismic ground velocity) at low spatial resolution. Fault models and long-term slip rates. | \n\t\t\tTime-series InSAR techniques as Persistent scatterers and Small Baseline. Non-linear inversion modeling. | \n\t\t||
Definition of maximum magnitude earthquake. | \n\t\t\tFault model geometry and kinematics. long-term slip rates. | \n\t\t\tNon-linear inversion modeling of deformation data. | \n\t\t||
Induced hazard | \n\t\t\tPre-event identification of gravitational slope deformations. | \n\t\t\tGeomorphological analysis. Long-term ground displacement rates at high spatial resolution. | \n\t\t\tAmplitude image interpretation and soil moisture analysis. Time-series InSAR techniques as Persistent scatterers and Small Baseline. Geomechanical modeling | \n\t\t|
Seismic vulnerability | \n\t\t\tIdentification of structural weaknesses in man-made structures. | \n\t\t\tLong-term ground displacement rates at very high spatial resolution. | \n\t\t\tTime-series InSAR techniques as Persistent scatterers. | \n\t\t|
\n\t\t\t\t | \n\t\t\tLoss estimation | \n\t\t\tRapid (1-2 days) spatial assessment of damage to man-made structures | \n\t\t\tMaps of damage classes at the district scale. Maps of collapsed structures at the single building scale. Very high resolution co-seismic ground displacements. | \n\t\t\tIntensity-based change detection and classification. Coherence-based change detection. | \n\t\t
Environmental damage estimation | \n\t\t\tRapid spatial assessment of environmental effects of earthquake: fault scarps, diffuse ground displacement, reactivated landslides, drainage reversal or interruption, soil liquefaction, sinkhole collapse, etc. | \n\t\t\tCo-seismic ground displacement maps at high spatial resolution. Geomorphological and structural analysis. | \n\t\t\tSAR Interferometry, pixel offset tracking, Multiple Aperture Interferometry, intensity image interpretation, coherence analysis. | \n\t\t|
Event scenario | \n\t\t\tRapid assessment of earthquake sources and possible evolution of the aftershock sequence. | \n\t\t\tCo-seismic ground displacement maps at medium-high spatial resolution. Geometrical and kinematic parameters of the earthquake sources. Stress increase on nearby faults. Post-seismic ground displacement for the next few months after the mainshock. | \n\t\t\tSAR Interferometry, pixel offset tracking, Multiple Aperture Interferometry. Time-series InSAR techniques. Non-linear and linear inversion modeling of deformation data. Coulomb stress analysis. | \n\t\t
Uses of SAR-derived information to support various components and actions of seismic risk management
Among the most important SAR-derived inter-seismic source parameters directly contributing to hazard estimates is the long-term slip rate. This is the yearly rate of slip which is modeled as occurring on the deep part of an active fault plane, below a given “locking depth”. The latter is defined as the depth separating the upper brittle crust, where the fault plane is locked, from the lower visco-elastic crust where the fault is instead slowly creeping, as explained in Section 4. If the region tectonics is dominated by a single large fault, as often is the case in plate margin contexts, the inversion of InSAR ground velocity measurements can be used to estimate the inter-seismic slip rate at depth.
The fault creep below the locking depth is in turn related to the stress build up in the upper crust, stress which will be eventually released during the seismic dislocation. Considering an ideal earthquake cycle, and assuming that the friction along the fault plane does not vary much through time, each successive fault rupture should occur when the accumulated shear stress overcomes a similar level of fault strength. Thus, the knowledge of the inter-seismic slip rate and of the seismic history of the fault should allow to estimate a recurrence time for moderate to large earthquakes on a given fault. These recurrence interval estimates have in some cases large uncertainties (fault strength and slip rates are indeed not constant through time), nonetheless the inter-seismic slip rates obtained by geodetic data (mainly InSAR and GPS), integrated with paleoseismological and seismological data, are considered important parameters to support seismic hazard calculations [95][96][97][98]. However, while GNSS data have been more extensively used (see for instance the SHARE EC project, the Working Group on California Earthquake Probabilities, 2011; [97]; [99]) to constrain the occurrence models for operational hazard assessment, InSAR data have so far been employed only marginally.
The reason why the inversion modeling of InSAR ground velocities is still not operationally used for the estimation of inter-seismic slip rates and other important fault parameters (as maximum magnitude earthquake), has to do with deficiencies in the data and with gaps in the underlying science. The inadequacy of present SAR system to provide useful data to measure small ground velocities over large spatial wavelengths has been addressed above, and it is expected to be partially resolved by the Sentinel-1 satellites. The scientific issues concern instead the incomplete knowledge of the processes driving the stress accumulation and release in the crust, which imply that the results of the models used to estimate active fault parameters through the inversion of inter-seismic ground velocities are are dependent on scientific judgment. In SHA, the uncertainties arising from the incomplete knowledge of the earthquake processes are addressed by ensuring that the generation of seismic hazard maps is based on discussions within the scientific community, aiming at developing the widest possible consensus on input data, methods, and practices [100]. We expect that in less than a decade the continuous InSAR data flow from the Sentinel-1 operational mission will have promoted the development of new inter-seismic source models, and better procedures for their significance and uncertainty assessment, effectively spreading the InSAR data use in SHA.
Two further important activities in seismic risk assessment/prevention in which SAR data can give a valuable contribution are (Table 1): 1) the identification of gravitational slope deformations which can undergo reactivation or catastrophic collapse during seismic shaking, and 2) the evaluation of the vulnerability level of buildings or infrastructures.
In the first case SAR imagery is used for two different purposes. The classical geomorphic photo-interpretation carried out also on optical images to detect the landforms indicating gravitational slope deformations, can be enhanced by the capacity of SAR intensity images to provide estimates of soil moisture [101]. In general these techniques are used to provide a spatial mapping of the landslide, with little information on its activity [102]. Another use relies instead on high resolution multi-temporal InSAR data to investigate the ongoing rates of gravitational mass movements in high seismic risk areas, which may be used to evaluate more specific hazard levels due to seismically-triggered landslide collapse [103]. The additional hazards induced by landslides reactivated by seismic shaking is very important especially in areas with high topographic relief: in the Wenchuan, 2008 earthquake over 20,000 casualties were attributed to landslide collapse [104].
Finally, a new field of use for InSAR-derived, high resolution ground deformation maps in the practice of seismic risk prevention, is to support a detailed vulnerability analysis in areas affected also by other deformation phenomena with high spatial frequencies (i.e. subsidence, sinkholes). If these phenomena occur in high seismic risk areas, the classification of the severity of the static deformation of man-made structures can allow a more accurate assessment of their resilience to future dynamic actions caused by seismic shaking.
The response phase of seismic risk management concerns all activities needed to promptly respond to the effects of a damaging earthquake. It can be divided in two main, temporally linked sub-phases, the Immediate response and the Sustained response [105].
During the Immediate Response phase, which usually lasts from few to several days, depending on the dimensions of the disaster, the main priorities are search and rescue actions and the emplacement of immediate preliminary measures to save lives and protect the population (evacuate insecure buildings and districts, provide emergency health services and food, install temporary shelters, etc.). A critical element for the management of this phase is the situational awareness, including all information on the extent of the phenomena (the event scenario), of its consequences (the loss scenario), and possibly future developments of both. Satellite SAR data can provide very important information in this phase, although, as we will see, the temporal requirements are difficult to fulfill.
After this initial phase the response actions are directed towards the return to an acceptable state of operation of human activities (repair or reinstall utility networks and infrastructures, provide more comfortable housing structures and working environments, provide temporary social services, etc.). This Sustained Response sub-phase may last from few to many months, and continuous information to monitor this lengthy process is required.
In the Response phase SAR data can be employed to generate two different families of products: those concerning the observation and quantitative measurement of the disaster effects on the human environment, and those providing information on the geophysical processes related to the phenomena (i.e. the earthquake and the triggered effects).
One of the main products of the first family is the damage assessment map, either provided at the district scale or at the single building scale [106]. While damage maps are also generated using data from optical satellites, which can provide higher resolution than SAR systems, the all-weather capability of the active microwave sensors provides an important advantage for rapid mapping in some regions [107]. Both types of data would require pre-and post-event imagery for an accurate change detection (post-event data only have been used, but with degraded accuracy), with SAR data having the additional constraint of the same looking geometry for the two acquisitions (mandatory for coherence-based detection techniques). Unfortunately, for very high resolution SAR and optical data, global coverage is neither continuous nor constant, and high resolution damage maps cannot be routinely generated. However, if ad hoc monitoring actions are started soon after the mainshock, the post-event images can be effectively used to incrementally map the further damage which may be caused by large aftershocks during the next weeks or months.
Where pre- and post-event, same-geometry SAR data do exist, InSAR techniques can provide accurate maps of co-seismic ground displacements. If very high resolution data are available (<3 m) these maps could be used to detect very localized damage to infrastructures (especially large, linear ones). The most common usage however is for the large scale mapping of ground movements directly related to the seismic dislocation (continuous ground displacement field and surface fault scarp), and for the mapping of local phenomena triggered by the seismic shaking (typically gravitational movements). During the Immediate response phase this information is extremely important to develop the situational awareness, for instance to direct rescue teams or implement safety measures; its value is however inversely related to the its delivery time after the mainshock. Depending on disaster size and location, a synoptic satellite map of a fault scarp or of the reactivated landslides may be outdated by more precise aerial or field surveys in 1-4 days. The co-seismic ground displacement map maintains instead its unique capacity to provide a high resolution image of the ground movement patterns which could not be provided by other means, critical for instance for the accurate mapping of gravitational movements, especially when earthquake-triggered accelerated motions are small and do not result in an immediate catastrophic collapse [5].
An additional important element of the situational awareness is the event scenario, which contains an analysis based on detailed information on the various geophysical variables (historical and instrumental seismicity, inter-seismic deformation, co-seismic deformation, local amplification effects, ground acceleration levels, stress transfer levels, etc.) and objects (earthquake source, nearby active faults, geological units prone to landsliding or liquefaction, etc.) which have an impact on the response actions [108].
As we have seen in section 3, the SAR-derived static co-seismic ground displacements are one of the most important datasets to constrain accurate models of the earthquake source [30]. The standard modeling techniques described previously can be implemented to operationally generate source models supporting event scenario development. Several source models (and event scenarios) may then be progressively generated during a seismic crisis, their quality improving as new seismological, geological, and InSAR observations become available and are jointly used to constrain the inversions.
As clearly shown by some recent cases (Emilia - Italy, 2012; Canterbury -New Zealand, 2010-2011, Balochistan - Pakistan, 2008; Umbria Marche - Italy, 1997; Southern California-USA, 1992), aftershocks can sometimes reach higher magnitude levels and cause stronger damage than the mainshocks [80][109][110][111]. As mentioned in Section 8 the triggering of large aftershocks can often be correlated to an increase of stress on nearby faults due the stress released by the mainshock dislocation and redistributed in the crustal volume. The co-seismic fault slip distribution generated by the linear inversion of InSAR data is used to calculate the variations of the Coulomb failure stress induced on the nearby active faults by each large earthquake occurring in a seismic crisis [80][109]. Even if the level of positive stress transfer cannot be used to deterministically quantify the clock-advance of failure on these faults, the knowledge of stress variations can be used to generate quantitative forecasts of aftershock productivity [66], providing important information for risk management during the response phase.
Another information product of interest for the Sustained response phase is provided by the InSAR monitoring of the post-seismic deformation, in particular that generated by poro-elastic diffusion and fault after-slip (Section 4). These ground movements may amount to few tens of percent of the co-seismic ones, and are expressed either as gradual slip increments occurring along the fault plane (at depth or at the surface), and as slow diffuse variations of the co-seismic ground displacement. They could increase the damage levels on man-made structures (e.g. linear rigid structures as viaducts or utility infrastructures), and should be monitored until they become negligible, usually within 7-12 months.
Given the rapid decay of this type of deformation, a dense InSAR temporal sampling is critical for its effective monitoring. For instance, using the full temporal sampling capacity of the COSMO-SkyMed constellation (~7 images per month) after 1.3 months the first time-series can be generated using multitemporal InSAR techniques (minimum dataset: 10 images), while the initial period can be monitored by classical two–pass InSAR. For lower sampling frequencies, the time-series analysis could begin too late, when much of the ground movements have already occurred: using Radarsat-2 for instance (1.25 image/month) 8 months are needed to accumulate a 10-image dataset, but even using a single Sentinel-1 satellite (2.5 image/month) the first deformation time series could be generated only after 4 months.
During the last 15 years, the importance of satellite Earth observation in disaster risk management has been acknowledged also through specific large scale technological programs, as the European Copernicus program (formerly Global Monitoring for Environment and Security - GMES), of which the new operational Sentinel satellites are the pillars. In this framework, an emergency management service has been developed since 2012 to provide mapping products for global-scale natural or man-made emergencies (GIO-EMS, http://emergency.copernicus.eu/). For earthquake emergencies GIO-EMS can be activated to provide rapid information products, as reference maps and damage assessment maps generated using optical and SAR data, to institutional users and national Civil Protection bodies.
A wider range of products, including all those described above, was demonstrated by the Italian SIGRIS system [108]. This is an Earth Observation monitoring system developed to generate information products based on various types of satellite imagery, to support the management of the seismic risk. The system development was promoted by the Italian Space Agency to exploit the potential of the Italian COSMO-SkyMed SAR satellite constellation, although other SAR and optical data are also used. The system requirements were provided by the Italian Civil Protection, which is presently the main user of the SIGRIS services. The system is now maintained and operated by INGV, a leading Italian geophysical research institute, which manages all the national ground-based networks for the monitoring of earthquake and volcanic phenomena and is also responsible for the production of the national hazard maps.
The SIGRIS system was conceived to provide both Assessment/Prevention and Crisis Response services, in support of various activities of the National Civil Protection Service, of which INGV is an integral part. It uses state-of-the-art InSAR and optical data processing and geophysical modeling algorithms, as well as validation/verification, reporting, and dissemination procedures, most of which are executed through a GIS-based interface.
The SIGRIS Assessment/Prevention service implemented the processing chain to generate most of the SAR-derived information products described in section 9.1, and the products were demonstrated in several test cases. Examples of the results derived from these products are shown in Figures 12 and 13.
Parameterization of a large blind active fault based on inversion modelling of inter-seismic, InSAR-derived deformation rates. The exact location, geometry and kinematics of the fault responsible for the M=7, 1908 Messina earthquake and tsunami is unknown. By modelling co-seismic levelling data, and inter-seismic GPS and InSAR deformation time-series, it has been possible to estimate some of the fault parameters. In green is indicated the freely slipping part, red shows the upper, locked part of the modelled fault. The final products for SHA are the slip rate=5 mm/yr, and the slip direction on fault plane (rake)=-125° (right normal kinematics).
Earthquake source model generated for the 2009, M=6.3 L\'Aquila earthquake, Central Italy, 12 days after the event.
The demonstration of the SIGRIS products for Assessment/Prevention confirmed that further improvements in the SAR data and in the geophysical modeling capacities (as mentioned in section 9.1) are needed before robust results can be generated on a routine basis. The new data provided by Sentinel-1, as well as by the ALOS-2, L-band SAR system, will be an important step towards both directions.
For the Response phase, SIGRIS contains processing chains and procedures to generate, validate and deliver the information products described in section 9.2. During the development phase, SIGRIS products were demonstrated for different areas of the world (www.sigris.it), but since 2011 the system is mainly activated for national earthquake emergencies.
Very positive has been the user evaluation of the quantitative, InSAR-based assessment of the co-seismic and post-seismic SIGRIS products, and especially for the earthquake source models. The system was used to obtain timely information products for the response phase of the L\'Aquila, 2009, Emilia, 2012, Pollino, 2012, and Lunigiana 2013, Italian earthquakes. The response products were delivered in successive versions with increasing information content. Usually the initial source models are based on fast, standard procedures for inversion and uncertainty assessment [59], while later models are constrained by a larger number of datasets and may involve the use of non-standard modeling techniques [27].
For all the mentioned events the SAR data were instrumental to the definition of the earthquake source, as GPS data were limited (L\'Aquila) or almost completely missing (Emilia, Pollino, Lunigiana), and provided minimum constraints for the modeling. Acknowledging the usefulness of COSMO-SkyMed InSAR data for Italian emergencies, in 2010 a routine acquisition plan was devised by the Italian Space Agency. The MapItaly plan is now operative to cover all of the Italian territory with a new acquisition every 16 days, providing the necessary, continuously updated archive, for all InSAR applications.
The use of SAR data has now become common practice among geophysicists involved in the monitoring and understanding of Solid Earth phenomena. By far the most important use of SAR data is for the measurement of surface ground displacements and for constraining models of crustal deformation.
Various scientific and commercial software packages are available for the data processing and for the modeling of the ground displacements, and in the last years a particular attention has been given to the integration of displacement data from InSAR and GPS, to cope with some of the inherent limitations of SAR systems, and augment the number of applications.
After the termination of ENVISAT-Asar, and ALOS-Palsar, in 2011, geophysical applications have suffered the lack of continuously updated archives, which the other national missions (Radarsat-2, TerraSAR X, COSMO-SkyMed) do not provide routinely over large areas. Great expectations are placed in the Sentinel-1 operational mission, which will provide at least two decades of high quality SAR data with constant and improved repeat pass over most of the emerged lands.
The enhanced characteristics of the Sentinel-1 system, as the larger swath, more precise orbit control, shorter repeat pass, improved resolution, open data access, will provide better and free data for all, increasing the diffusion of SAR data use in Solid Earth Geophysics. Thus the next decades are bound to see new science, better interpretation methods, and more effective operational applications based on Synthetic Aperture Radar.
Standard examination of human semen currently remains a main test for male fertility disorders. The concentration (total sperm count) and motility of spermatozoa and the content of morphologically normal (typical) spermatozoa are thought to reflect the fertilization potential of the semen [1]. Although their values in fertile men are generally higher than in sterile ones, there is a substantial overlap between the two populations, indicating that other important factors affect fertility, but are not assessed in conventional assay [2]. In this regard, methods to assess the functional properties of spermatozoa and thus to evaluate their reproductive (fertilizing) potential have intensely been developed in the past years.
Light microscopy, which is employed in a conventional sperm testing, reports the numbers of sperm heads and tails, their sizes and relative arrangement, the presence and sizes of the acrosome and nuclear vacuole, and sperm movement. An ultrastructural examination makes it possible to look inside the spermatozoon and to study what is inaccessible by light microscopy, including the extent of chromatin condensation and the structures of the perinuclear theca (PT), its postacrosomal segment, the centriole, the axoneme, and periaxonemal elements of the tail.
Every function of the spermatozoon is now possible to attribute to a particular morphological structure owing to the achievements of modern molecular biology, cytology, and genetics. The morphology of spermatozoa reflects how competent they are to fertilize (enter) the oocyte and to provide for embryo development.
The nucleus occupies a major part of the sperm head and contains condensed chromatin (Figure 1a), which is detected as an electron-dense homogeneous material, with small regions of lower electron density on ultrathin sections. Condensed chromatin is at least 10 times denser than ones in somatic cells [3].
(a) Spermatozoon with condensed chromatin (CH) and normal acrosome (A). (b) Postacrosomal segment of perinuclear theca (PS) with characteristic intermittent striation. (c, d) Spermatozoon with immature chromatin (IC). (e) Fragment of sperm acrosome. NE, nuclear envelope; PT, perinuclear theca; IM, inner acrosome membrane; EM, extra acrosome membrane; and PM, plasma membrane.
To achieve this unique extent of compaction, sperm DNA is packaged in a specific manner, which substantially differs from chromatin packaging in somatic cells. In somatic cells, DNA is packaged to produce the so-called nucleosomes. The DNA double helix is wrapped around a specific complex of canonical histones (a histone octamer) [4].
During sperm maturation, canonical histones are replaced by testis-specific histones and then by protamines, basic proteins with lower molecular weight and high concentration of arginine and cysteine (for a review, see [5, 6]).
As spermatozoa progress through the epididymis, disulfide bridges form between cysteine residues of protamines to further stabilize the DNA-protamine complex and morphologically determine condensation of the dense nucleoprotamine complex in the sperm nucleus [7]. Sperm chromatin is decondensed and acquires a nucleosomal structure after fertilization. The organization of sperm chromatin facilitates the transfer of compacted DNA into the oocyte and ensures its reverse transformation so that genetic information becomes readily available in the developing embryo [8].
Approximately 5–10% of genomic DNA remains free of protamines and preserves a nucleosomal structure in mature human spermatozoa (for a review, see [9]). The role of the residual nucleosomes remained unclear until recently and was explained in three studies, which were published simultaneously in 2010 [10, 11, 12]. Residual nucleosomes were found to mark the genes for early embryo development factors and to perform an important function in the epigenetic regulation of embryo development. A gene distribution between protamine-associated and histone-containing (nucleosomal) regions of chromatin follows a certain pattern. Residual nucleosomes occur in the promoters of early developmental genes (e.g.,
Condensation associated with histone-to-protamine replacement metabolically inactivates chromatin and, on the other hand, contributes to its mechanical and chemical stability, thus protecting the paternal genome from nucleases while spermatozoa travel through the male and female reproductive tracts and interact with the oocyte. Residual nucleosomes mark early developmental genes. Normal chromatin condensation is indicative of the sperm potential to produce a normally developing embryo.
Spermatozoa with incomplete chromatin condensation in the nucleus are almost always detectable in ejaculate samples from fertile donors. Granular and fibrillary structures of approximately 40 nm in diameter are seen in these cells. The chromatin structure observed in the spermatozoa is similar to that of elongated spermatids, and their chromatin is consequently known as immature chromatin (Figure 1c, d) [13].
What is a possible role of distorted chromatin compaction? The disturbance of chromatin condensation is a consequence of a reduced protamine content [14]. Hammoud et al. [15] have recently found that defects in histone-to-protamine exchange lead to a random distribution of nucleosomal (histone-associated and potentially active) chromatin in infertile patients, in contrast to a programmed nucleosomal chromatin distribution in fertile men. Distorted chromatin compaction in spermatozoa seems to lead to substantial post-fertilization defects. Abnormal (insufficient) chromatin condensation was shown to delay the first cell division cycle and to subsequently cause damage to the embryo [16]. Such defects can be responsible for ART failures [17] and early pregnancy losses [18].
Higher percentage of spermatozoa with immature chromatin was observed in semen of the patients with arrest of embryonic development compared with fertile men, and the difference was statistically significant. Semen samples with increased percentage of spermatozoa with immature chromatin in the men with embryo development arrest in reproductive history were 2.2 times more frequent than in the control group (44 vs. 20%) [19].
The question arises as to whether defects in chromatin condensation are associated with DNA fragmentation in spermatozoa. An early hypothesis suggested that defects in histone-to-protamine exchange and, therefore, in chromatin condensation inevitably lead to higher sperm DNA fragmentation [20].
A higher count of spermatozoa with immature, insufficiently condensed chromatin in semen provides an independent diagnostic sign and shows no association with a higher count of spermatozoa with DNA fragmentation [19, 21]. Clinically, fertility disorders are associated with both higher percentage of spermatozoa with immature chromatin and higher percentage of spermatozoa with DNA fragmentation in the ejaculate, but the disorders differ in nature between the two cases. Diagnosing the nature of damage to sperm nuclear material makes it possible to choose a treatment adequate to the observed defect [22].
Hollows, which were initially described as vacuoles varying in size and location, can be detected in chromatin of sperm nuclei [23]. Vacuoles are actually indentations in the nucleus, as is seen on ultrathin sections. Chemes and Alvarez Sedò [24] have proposed the term lacunae or lacunar defects for nuclear vacuoles. Lacunae vary in location and texture. Figure 2a, b shows a lacuna surrounded by a membrane with membrane whorls (MWs), which consist of double membranes with septal complexes [25]; the lacuna is interconnected with nuclear pockets at the base of the head (Figure 1a).
Vacuoles in the sperm nucleus. The lacuna surrounded by membrane with membrane whorls (MWs) (a, b). The lacuna is interconnected with nuclear pockets at the base of the head (a, arrow). Invaginations of the nucleus (I) not surrounded by membrane (d, e), and two large lacunae (L) without visible contact with the subacrosomal space (c). A, acrosome and PS, postacrosomal segment of perinuclear theca.
Invaginations of another type can also be detected in sperm nuclei. The invaginations may occur in both basal and apical parts of the nucleus, are not surrounded by a membrane, and contain granular material (Figure 2d, e). A connection (contact) between a lacuna and the subacrosomal space cannot always be seen in ultrathin sections, and the lacuna consequently appears to be a vacuole in nuclear chromatin. DNA is absent from lacunae (Figure 2c) [26].
Moving sperm organelle morphology examination (MSOME) using high-resolution microscopy at magnifications exceeding 5000× makes it possible to select in vivo the vacuole-free spermatozoa and to perform intracytoplasmic morphologically selected sperm injection (IMSI) [27].
There are data that IMSI of spermatozoa without vacuoles or with one small vacuole substantially increases the yield of blastocysts as compared with spermatozoa containing large vacuoles or spermatozoa with more than two small vacuoles [28].
On the other hand, no correlation of the presence of large vacuoles in spermatozoa has been observed for spermiogram parameters, DNA damage, and live birth rate [29]. IMSI does not improve the outcome of ART after two successive IVF-ICSI failures [30].
Haraguchi et al. [31] have used immunochemistry with electron microscopy and detected proteasomes in nuclear vacuoles and clear spots of condensed chromatin. Nuclear vacuoles and nuclear pockets at the base of the nucleus were assumed to function as proteolytic centers to resorb the molecules (somatic and sperm-specific histones and transit proteins) that are released during chromatin reprogramming. A positive correlation between the presence of vacuoles and the acrosomal reaction [32], vacuoles and capacitation [33] similarly indicates that vacuoles are related to physiological properties of spermatozoa and has no effect on their fertilizing potential.
The acrosome is a secretory vesicle derived from the Golgi apparatus. The acrosome forms a cap on the anterior pole of the nucleus and consists of an outer membrane, inner membrane, and matrix. The outer acrosomal membrane is adjacent to the plasma membrane covering the head of the spermatozoon. A layer sandwiched between the inner acrosomal membrane and the nuclear envelope is known as the perinuclear theca (PT), which has a medium electron density and is approximately 200 nm thick (Figure 1e).
The acrosome covers the anterior two-thirds of the sperm head. Relative to the acrosome, the head can be divided into three regions: acrosomal, equatorial, and postacrosomal. Only the PT with its characteristic intermittent striation occurs between the nucleus and the plasma membrane in the postacrosomal region of the spermatozoon (Figure 1b).
Material contained in the lumen of the acrosome has a medium electron density and is known as the acrosomal matrix [34]. Zona pellucida (ZP)-binding proteins are found in the acrosomal matrix. Proacrosin is the most important of all ZP-binding proteins of the acrosome. Proacrosin was long believed to be a main lytic protein essential for sperm penetration through the ZP. However, proacrosin knockout mice were found to be fertile [35], although their spermatozoa penetrate through the ZP slower than spermatozoa of wild-type mice. Acrosin probably plays a role in maturation and packaging of other acrosomal matrix proteins. The acrosomal matrix contains several other ZP-binding proteins.
The acrosome of a capacitated spermatozoon interacts with ZP glycoprotein 1 (ZP1) of the oocyte to trigger fusion of the plasma and outer acrosomal membranes, the membrane ends fuse, and vesicles form. Then proteases are released from the acrosome and digest the ZP. The process is known as the acrosomal reaction, which consists in exocytosis and allows the spermatozoon to pass through the ZP. Acrosome-reacted spermatozoa subsequently bind with ZP2, another glycoprotein, which is responsible for sperm adhesion to the oocyte [36]. The inner acrosomal membrane remains intact.
The plasma membrane and the outer acrosomal membrane of the equatorial segment are not involved in forming vesicles during the acrosomal reaction. The equatorial segment is a region where fusion of the spermatozoon and oocyte plasma membrane is triggered. The sperm plasma membrane of the equatorial segment fuses with microvilli of the oolemma, the membranes fuse, and sperm components are thus delivered into the ooplasm. The equatorial segment protein (ESP) is found in the equatorial segment of the acrosome in human spermatozoa [37]. ESP is detectable throughout the acrosome biogenesis. It is thought that ESP plays a role in adhesion of the spermatozoon to the oocyte and their fusion at the oolemma level. Fujihara et al. [38] identified sperm equatorial segment protein 1 (SPESP1), which is specific to the equatorial segment. Spermatozoa of transgenic mice devoid of
An important role is ascribed to Izumo. The Izumo family includes four proteins, Izumo1-4. Izumo1 is a membrane immunoglobulin protein with an extracellular immunoglobulin domain of 145 residues and an N-terminal domain. The sperm protein Izumo1 on the equatorial segment of the acrosome-reacted spermatozoon recognizes its receptor, JUNO, on the oocyte surface. Human Izumo1 forms a high-affinity complex with the Juno receptor of the oocyte and changes its conformation [39].
The PT is a cytoskeletal structure that harbors a specific oocyte-activating factor (for a review, see [40]). The PT and its postacrosomal segment remain associated with the sperm nucleus and enter the oocyte upon fertilization. In contrast to the acrosome, which rapidly responds to exogenous factors, the PT is resistant to extraction with denaturing agents and high-salt buffers.
The putative oocyte-activating factor MN13 was found in the PT [40]. MN13 is located in periodic striations, which form the postacrosomal sheath of the PT.
Phospholipase C zeta (PLCζ) is another protein found in the postacrosomal segment of the PT and is thought to act as an oocyte-activating factor [41].
Thus, PLCζ and probably other proteins of the postacrosomal sheath of the PT act as oocyte-activating factors. The postacrosomal sheath is the first to contact the oocyte, and its dissolution (disassembly) is sufficient for triggering early events of oocyte activation. The oocyte-activating factors are transmitted from the sperm PT into the oocyte cytoplasm after the incorporation and rapid dissolution of the PT. In the normal fertilization cycle, the PT dissolves in the oocyte cytoplasm simultaneously with decondensation of the sperm nucleus and initiates division of the maternal pronucleus by hydrolyzing a membrane-bound phospholipid substrate, triggering cytoplasmic Ca2+ oscillations [42]. In the case of ICSI, activation occurs only in the oocytes that contain a partly or completely dissolved PT. When the PT dissolves only partly, the residual PT postacrosomal sheath may persist at the apical side of the paternal pronucleus and may delay or arrest zygote development [43]. Dissolution of the subacrosomal part of the PT is essential for complete DNA decondensation in the paternal pronucleus and the start of DNA synthesis in both pronuclei.
Electron microscopic examination of the acrosome provides an experimentally grounded alternative to sperm penetration assays. The method reliably reports the integrity of the acrosome and the status of its enzymatic system and the postacrosomal segment, which is involved in sperm attachment to the oocyte. A higher percentage of spermatozoa with abnormal acrosomes in an ejaculate sample can be responsible for idiopathic infertility when the spermiogram parameters are within the normal ranges.
Lack of an acrosome is identified as primary when resulting from spermiogenesis defects. Globozoospermia of a presumably genetic nature provides a classical example of the primary lack of an acrosome.
Globozoospermia is an uncommon male fertility disorder. Round-headed cells may account for up to 6% of the total sperm count in the ejaculate in fertile men [44], while 100% of spermatozoa have round heads in total globozoospermia. The sperm count and motility are not affected in globozoospermia. An ultrastructural examination shows that acrosomes are completely absent from round heads or that a rudimentary acrosome occurs at the nuclear pole opposite to the tail (Figure 3a).
(a) Round acrosomeless sperm heads from globozoospermia. Some nuclei are with condensed chromatin (CH) and one nucleus with immature chromatin (IC). (b) Secondary lack of acrosome. The intact internal acrosomal membrane (IM) and postacrosomal segment (PS) are visible. The outer acrosomal membrane and the plasma membrane form bubbles (B). (c) Acrosome with irregular contours (RA); (d) “empty” acrosome (EA).
Defects of chromatin condensation in the nucleus are additionally seen in the majority of ejaculate samples. Heterogeneity is also possible; i.e., spermatozoa with normal condensed chromatin and those with decondensed chromatin may be detected in one ejaculate sample. Both within- and between-sample heterogeneity are observed. Higher contents of spermatozoa with immature chromatin [45] were observed in globozoospermia in the majority of studies.
Kullander and Rausing [46] were the first to assume a genetic nature for globozoospermia. Cases with a family history of the disorder supported the assumption. Mutations or deletions of three genes—
The identification of the missense mutation L967Q of the gene
The postacrosomal sheath of the PT is absent in patients with globozoospermia. PLCζ is found in extremely small, if any, amounts in spermatozoa of mice and human patients with a
Secondary lack of an acrosome results from a premature acrosomal reaction, i.e., the acrosome is lost in acrosome-reacted spermatozoa (Figure 3b). Disruption of the plasma membrane is observed in this case, and the inner acrosomal membrane adjacent to the nuclear envelope is seen on the sperm surface in the acrosomal region. The outer acrosomal membrane and the plasma membrane form bubbles during the acrosomal reaction. In the case of a physiological acrosomal reaction, the postacrosomal segment and its plasma membrane are preserved in the live spermatozoon.
The percentage of spermatozoa with a secondary loss of the acrosome (i.e., acrosome-reacted spermatozoa) in ejaculate samples are 18.22 ± 8.27% in fertile men and 26.37 ± 12.81% in infertile patients with normal spermiogram parameters (p < 0.05) [52]. A higher percentage of acrosome-reacted spermatozoa (with acrosome degradation) in the ejaculate may impair its fertilization potential. Leukocytospermia with an enhanced production of reactive oxygen species by leukocytes is one of the possible causes of an early acrosomal reaction. Our findings indicate that bacterial microcolonies present in the ejaculate may also cause a premature acrosomal reaction, and their presence is not always accompanied by an inflammatory response. We analyzed the results of electron microscopic examinations of 746 semen samples from patients with fertility disorders. Bacterial microcolonies were detected in 186 of the 746 samples (25%), and a higher (more than 20%) content of spermatozoa with a secondary loss of the acrosome was observed in 112 of the 186 samples (60%). In the absence of bacterial infection, a higher content of acrosome-reacted spermatozoa was found in 117 of the 560 samples (20%) [55].
A higher leukocyte count in the ejaculate was detected in 36 of the 186 samples with bacterial microcolonies (19%).
Electron microscopy is a gold-standard test for acrosomal reaction, although a number of other tests are now available to assess the penetrating potential of spermatozoa.
Irregular acrosome (Figure 3c) and lack of acrosomal contents (Figure 3d) (enzymatic insufficiency of the acrosome) are found in both pronounced teratozoospermia and normospermia. Proteolytic enzymes of the acrosome dissolve the zona pellucida to allow fusion of the spermatozoon and the oolemma. When the process is disturbed as a result of acrosome loss or dysfunction, spermatozoa lose their fertilizing potential. Irregularly T-shaped acrosomes can be detected in binuclear spermatozoa (Figure 4a).
(a) Binuclear spermatozoa with T-shaped acrosome (TA). (b) Sperm with small cytoplasmic droplet on the head (CD) lacking the PT and its postacrosomal segment and with enlarged subacrosomal space (SS). A, irregular acrosome. (c, d) Spermatozoa with excess residual cytoplasm on the head (RH) and on the neck (RN), irregular acrosomes (A), and enlarged subacrosomal space (SS).
Spermatozoa that have an enlarged perinuclear space and lack the postacrosomal sheath of the PT account for 2–5% of the total sperm count in semen from fertile men (Figure 4b–d). The abnormality is often combined with the presence of excess residual cytoplasm on the head (Figure 4c, d). The disorder is sometimes referred to as type II globozoospermia. Sperm heads appear to be spherical under a light microscope, but an ultrastructural study shows that spermatozoa have normal elongate nuclei, whereas their heads look round because of excess residual cytoplasm. This form of pathology also impairs fertility, but differs from globozoospermia [56] because lack of the PT and its postacrosomal segment suggests lack of the oocyte-activating factor.
In some cases, a small cytoplasmic droplet on the head is found in spermatozoa lacking the PT and its postacrosomal segment, so that the spermatozoa appear to be normal by light microscopy (Figure 4b). The pathology is detectable only by electron microscopy and may cause idiopathic infertility while the conventional spermiogram parameters are within the normal ranges. ICSI with the oocyte activation methods developed for patients with globozoospermia could solve the problem for these patients. A promising method was tested in a mouse model; i.e., recombinant PLCζ was injected to allow fertilization with spermatozoa of
The acrosome is the most labile component of the spermatozoon. According to our data, the percentage of spermatozoa with abnormal acrosome shapes is 50.12 ± 8.70% in fertile men. Alterations of the acrosome shape or lack of the acrosomal contents are greater in men with fertility disorders. Acrosomal hypoplasia is a common component of pronounced teratozoospermia, is well detectable by electron microscopy, and is essential to diagnose because acrosomal insufficiency is possible to correct using ICSI (for a review, see [58]).
The connecting piece connects the head with the tail (Figure 5a). A thin basal plate occurs at the base of the head, it has a concave shape, forming an implantation fossa. The region beneath the basal plate harbors nine striated columns, which continue caudally as outer dense fibers. Striated columns are the part of the connecting structures of the neck. The basal plate is at the base of the head nucleus. A centriole is enclosed in an electron-dense capitulum. The centriole is a universal element of animal eukaryotic cells and plays a role in the formation of the mitotic spindle.
(a) The connecting piece of normal spermatozoon. (b) Decapitated spermatozoon. B, basal plate; C, centriole; Ca, capitulum; SC, striated column, OF, outer dense fibers; and M, mitochondria. (c) Transverse section through the mid-piece of spermatozoon tail; (d) transverse section through the principal piece of spermatozoon; (e) longitudinal section through the middle and principal piece of the tail; (f) the site of contact between mitochondria (arrow). Ax, axoneme, dynein arms of peripheral microtubule doublets are visible. M, mitochondria; FS, fibrous sheath; and An, annulus.
A typical centrosome (cell center) of immature germline cells consists of two cylindrical centrioles, each consists of nine symmetrically oriented microtubule triplets, of 0.5 μm in length and 0.2 μm in diameter. Two centrioles are positioned in an orthogonal orientation, the axis of the daughter centriole being perpendicular to that of the mother centriole. A typical centriole has a 9 + 0 organization of microtubule triplets. In a mature spermatozoon, the distal centriole gives origin to the tail axoneme and is reduced. The proximal centriole preserves its morphology, enters the oocyte upon fertilization, and plays a role in organizing the cleavage spindle [59].
The centriole is surrounded by striated columns, which are part of the connecting structures of the neck. The basal plate is at the base of the head nucleus. The centriole is capable of functioning as an organizing center during cell division only when having a normal morphology, as was demonstrated in many somatic cell studies [60].
The role of the sperm centriole has come into focus of research relatively recently, with the development of ART methods. A paternal inheritance of the centriole was then demonstrated for humans and large mammals as opposed to rodents [61]. The centriole organizes microtubule assembly to produce the sperm aster, which forms around the paternal pronucleus 6 h after fertilization [62] and gives origin to the first mitotic spindle. The main function of the centriole is to organize a network of microtubules, which originate from the oocyte.
Centrosome abnormalities were described as a cause of unsuccessful fertilization and abnormal embryo development [61, 62]. Decaudated or decapitated sperm is a rare syndrome in humans and includes the absence of the implantation fossa and the basal plate. Morphological features of the human syndrome were described comprehensively, and ultrastructural defects of spermatozoa with an abnormal fragility of the head-tail junction were studied by electron microscopy (Figure 5b). The proximal centriole/centrosome, which induces the formation of the basal plate and the implantation fossa, was assumed to play an essential role in attaching the flagellum to the nucleus. Dysfunction of the proximal centriole/centrosome may alter the formation of tail attachment structures, leading to decapitated sperm. Spontaneous fertilization is impossible with such spermatozoa because the tail easily detaches from the head because of the neck fragility. ICSI is the only way of fertilization in this case, but rarely is successful. Chemes et al. [63] observed lack of cleavage after ICSI. Porcu et al. [64] reported successful ICSI in two infertile couples where the men were brothers and produced acephalic spermatozoa or spermatozoa with abnormal head-tail attachments, and one birth was published by Gambera et al. [65].
A genetic origin is now commonly accepted for the syndrome. Baccetti et al. [66] assumed that recessive autosomal mutations account for the majority of sperm genetic defects. However, the genes affected by the mutations are unknown. Light microscopic signs of the syndrome vary. Multiple motile tails with single, if any, tailless heads are observed in semen in the majority of cases. Kamal et al. [67] described 16 cases with a variant of the syndrome wherein the spermiogram parameters were normal, while minimal ICSI-related manipulations caused decapitation and immobilization of spermatozoa. The head and tail usually separate at the head-neck junction; the connecting piece is preserved; the basal plate and implantation fossa are absent from the caudal pole of the nucleus.
Several variants of decapitated sperm were described. Holstein et al. [68] reported a case where the basal plate and implantation fossa were normal in morphology, while separation occurred between the proximal and distal centrioles. Baccetti et al. [66] described a patient with sperm ruptures occurring between the nucleus and centriole region, between the anterior and caudal regions of the mid-piece, and between the mid-piece and principal piece. A number of variants are most likely possible for sperm decapitation.
Cases of familial incidence of teratozoospermia with acephalic sperm suggested a genetic nature for the disorder [69]. Homo- or heterozygous mutations of the spermatid-specific SUN5 gene were found in some patients with acephalic (decapitated) sperm syndrome [70]. The protein product of the gene occurs in the immediate vicinity of the head-tail junction, and proteins of its family are known as part of the contact system that connects the inner nuclear membrane with the cytoskeleton.
The intact tail of a human spermatozoon is approximately 50 μm in length and consists of four regions: a connecting piece, which is attached to the head; a mid-piece, which is 3–5 μm long; a principal piece, which accounts for approximately two-thirds of the tail length; and a short end piece. In contrast to cilia, which are covered by the plasma membrane, the sperm tail has not only the axoneme but also additional structures that surround the axoneme and are known as the periaxonemal structures. A mitochondrial helix and outer dense fibers surround the axoneme in the mid-piece and a fibrous sheath in the principal piece. The axoneme has no periaxonemal structures only in the short end piece.
The axoneme forms a core in cilia and flagella. The sperm axoneme consists of nine pairs of microtubules (doublets) that are arranged in a ring around two central singlet microtubules (9 + 2 arrangement). The doublets are numbered clockwise, starting from the site where two doublets overlay the central pair of microtubules; the right doublet is number one (Figure 5c, d). Each peripheral doublet consists of a complete microtubule (subunit A) and an adjacent incomplete microtubule (subunit B).
Two, outer and inner, arms consisting of the protein dynein (dynein arms) with ATPase activity extend from the A subunit of each doublet towards the B subunit of the next clockwise doublet. Each dynein arm is an intricate multiprotein complex and acts as a molecular motor [71]. The microtubule doublets are connected via thin bridges of the protein nexin (nexin bridges) and project radial spokes towards the two central microtubules. This sophisticated structure sustains sliding movements of the microtubules, thus providing for undulations of the tail. The axoneme is intricate molecular machinery wherein the inner and outer dynein arms generate forces to produce bending waves and the central apparatus and radial spokes play a regulatory role [72, 73].
The outer dense fibers are a morphological extension of the striated columns and capitulum, which are structural elements of the connecting piece of the sperm neck [74]. The outer dense fibers surround the axoneme in the mid-piece of the tail, one fiber overlaying one peripheral microtubule doublet. ODF1 is a major protein of the outer dense fibers (Figure 5c, e).
The number of mitochondria is reduced as a large portion of the cytoplasm is eliminated with residual bodies from spermatids in the course of spermiogenesis [75]. Up to 75 mitochondria are left in a mature spermatozoon with a minor cytoplasm amount and form a helix around the outer dense fibers and axoneme. The mitochondrial helix has 11–13 turns with two mitochondria per turn. The mitochondrial helix length and the approximate number of turns are constant within a species [76].
The structure of the mitochondrial helix is stable owing to the so-called mitochondrial capsule, i.e., the outer mitochondrial membrane is coated with keratin-like molecules, which form disulfide bridges between cysteine- and proline-rich selenoprotein regions [77]. Contact zones form at the sites of contacts between mitochondria, indicating that the spermatozoon has a mitochondrial reticulum, similar to the mitochondrial network of the heart muscle rather than individual mitochondria (Figure 5f) [78, 79].
Active functional mitochondria were demonstrated to affect the sperm fertilizing potential in many studies. Ultrastructural defects in mitochondria are associated with lower sperm motility. The available data on the role of mtDNA mutations are discrepant. Deletions from mtDNA were considered to be responsible for sperm dysfunction and infertility [80]. However, the difference was not confirmed for several mtRNAs by rtPCR.
Metabolism of sperm mitochondria is still a matter of discussion. It is commonly accepted that ATP produced by mitochondria provides a main source of energy for the dynein motor of the axoneme. In contrast, a compartmentalization hypothesis suggests that glycolysis is a main source of energy for tail movements [81]. Because discrepant experimental data were reported from different studies, the question is still open. It is possible that mitochondria are involved in basic redox processes, which determine the fertilizing potential and lifespan of the spermatozoon, rather than in energy metabolism as a main function.
The mid-piece and principal piece of the tail are separated by a ring structure known as the annulus (Figure 5e), which presumably performs a barrier function to prevent molecular diffusion between the two pieces [82].
The principal piece of the tail is distal of the mid-piece and is the longest tail segment. The mitochondrial sheath is not found in the principal piece, and a fibrous sheath as another cytoskeletal element of the tail surrounds the axoneme. Two longitudinal columns of the fibrous sheath replace two opposite outer dense fibers and are connected together by numerous circumferential ribs (Figure 5d, e).
A total of 18 polypeptides were identified in the fibrous sheath. The polypeptides form a scaffold for glycolytic enzymes and act as signaling molecules upon induction of sperm motility (for a review, see [83]). A-kinase anchoring proteins 3 and 4 (AKAP3 and AKAP4) are major components of the fibrous sheath and probably form its integral cytoskeletal structure. AKAP3 and AKAP4 are associated with each other and bind to cAMP-dependent protein kinase A through its regulatory subunit. The AKAP3 and AKAP4 genes were sequenced, and the binding sites identified.
The principal piece of the tail harbors glycolytic enzymes, including sperm-specific hexokinase 1, lactate dehydrogenase, and sperm-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDHs) [84].
The complex system of tail elements with their concerted function provides the spermatozoon with the ability to move, that is, to reach and fertilize the oocyte. Any structural alteration of the system impairs sperm motility.
A functional variant of asthenozoospermia is the most common. Spermatozoa of patients display multiple heterogeneous ultrastructural changes in the axoneme and periaxonemal structures (Figure 6a–e), such as changes in the number and arrangement of the microtubule doublets, the shape of the outer dense fibers, or the architecture of the fibrous sheath. Quantitative changes in mitochondria and their altered localization were also associated with asthenozoospermia. The percentage of spermatozoa with ultrastructural tail defects is significantly higher in patients with asthenozoospermia. Ultrastructural defects of the tail axoneme were described in drug addicts [85]. Yet smoking and alcohol drinking were not found to affect the ultrastructural parameters of mature spermatozoa, lower sperm counts observed in alcoholics and smokers suggest testicular selection [86]. Functional asthenozoospermia can be secondary to a varicocele, infections of reproductive organs, and exogenous exposures [58]. Spermiogram parameters are possible to correct with medications in men diagnosed with functional asthenozoospermia. When the treatment is ineffective, ICSI is likely to help.
Longitudinal (a, b) and transverse (c–e) sections through abnormal sperm tails. (a) Lack of annulus (arrow) between the middle and principal piece of the tail; (b)swollen mitochondria (SM) and dislocation of mitochondria (arrow); (c) normal axonema structure and increased quantity of outer dense fibers (OF); (d) disorganization of axonemal microtubules (MT) and outer dense fibers (OF); (e) double tail with (9 + 1) microtubules. The absence of dynein arms in the right axoneme is revealed. FS, fibrous sheath.
Chemes et al. [87] proposed the term dysplasia of the fibrous sheath (DFS) for the disorder, which is also known as stump tail syndrome and short-tail spermatozoa. Spermatozoa have substantially reduced, if any, motility due to fibrous for DSF [88]. In spermatozoa, the location of longitudinal columns and transverse ribs of the fibrous layer has been disturbed. There are changes in the structure of the mitochondrial helix—a significant shortening and disruption of localization. Anomalies in the structure of the fibrous sheath often put together with the absence of a central pair of the axoneme microtubules (Figure 7a–c).
(a) Sperm with dysplasia of the fibrous sheath (DFS) of the tail. The lack of mitochondria is revealed (arrow). Transverse (b) and longitudinal (c) sections through the tail with DFS. The lack of the central pair of microtubules (asterisk). (d) Sperm with primary ciliary dyskinesia (PCD). Transverse (e) and longitudinal (f) sections through the tail with PCD. The absence of dynein arms is revealed on the transverse section. OF, outer dense fibers; FS, fibrous sheath; and M, mitochondria.
A mouse model of DFS was obtained by targeted disruption of the
We found a decrease in the activity of the glycolytic sperm-specific enzyme glyceraldehyde-3-phosphate dehydrogenase (sGAPD) and atypical localization of the enzyme. Mutations within human
DSF has an autosomal recessive inheritance. The genetic risk is now impossible to estimate. A few cases of live births after ICSI with spermatozoa of DSF patients were reported in the medical literature [93].
PCD is an autosomal recessive disorder and is highly heterogeneous genetically. PCD affects the axonemal structures (microtubules and dynein arms) of cilia and flagella (Figure 7d–f). Bronchial and pulmonary diseases are the main pathology in PCD because infections and bronchiectasis develop when respiratory cilia have motility defects or are immotile.
Headaches are common in PCD patients because lack of ciliary motility in the brain ventricles impairs circulation of the cerebrospinal fluid. Situs inversus is additionally observed in half of the PCD patients, possibly resulting from lack of ciliary motility in embryonic Hensen’s node, which is responsible for the unidirectional fluid flow and thereby establishes left-right asymmetry [94]. The prevalence of PCD at birth is 1/10,000 to 1/20,000 [95].
Fertility is impaired in male patients because their spermatozoa are absolutely immotile or defects occur in efferent seminiferous ducts lined by ciliated epithelia. In a semen analysis, gross ejaculate parameters (volume, pH, viscosity, and color) and the concentration and count of morphologically normal spermatozoa are within the normal ranges.
Transmission electron microscopy (TEM) is commonly used to detect PCD. TEM reports lack of outer and/or inner dynein arms, the two central microtubules, or radial spokes and changes in microtubule arrangement.
Molecular methods to diagnose PCD have intensely been developed in the past years. Unicellular algae of the genus Chlamydomonas, which have two flagella, provide a convenient model to study the molecular composition of the axoneme. Axoneme protein genes identified in Chlamydomonas are candidate genes for PCD. A total of 16 mutations of PCD candidate genes were identified from 1999 to 2011 by genetic methods (analysis of linkage groups identified by homozygosity mapping), proteome analysis, and sequencing (mostly Sanger sequencing). Since 2011, mutations of 18 other genes have been described via whole-exome and whole-genome sequencing (for the review see [73, 96]).
PCD is genetically heterogeneous. Mutations of two genes,
Many proteins are involved in building the axoneme. Several proteins are common for epithelial cilia and sperm tails. Patients homozygous for mutations of their genes develop the total set of PCD signs, including bronchial and pulmonary diseases, changes in asymmetry of visceral organs, and immotile sperm. Other axonemal proteins are tissue specific, and mutations of their genes cause mosaic ciliopathy, such as asthenozoospermia and anosmia, or asthenozoospermia and swelling of the nasopharyngeal mucosa, which we identified in our patients.
The development of ICSI allowed men with pronounced asthenozoospermia, including forms with genetic causes, to have children. The consequences of using ICSI in PCD and DSF are poorly understood because the disorders are rare and only few live births after ICSI have been reported (20 cases according to PubMed). PCD patients with andrological symptoms naturally had no offspring before the advent of ICSI. PCD is an autosomal recessive disorder and is expressed only in homozygotes and compound heterozygotes, when both alleles of one gene are affected. This circumstance reduces PCD risk in ICSI offspring, but makes it more likely for the mutations to accumulate in the population and to occur in homozygote at a higher rate in the long term.
Virus capsids morphologically identical to capsids of
(a) Longitudinal section of normal sperm; (b) section through the middle piece of the tail of sperm. VC, HSV capsids; M, mitochondria; A, acrosome; CH, chromatin; and C, centriole. The hexagonal structure of some capsids is visible. Phase-contrast microscopy (c) and IF (d) of infected sperm. HSV antigen (arrows) and DAPI stain for DNA (blue); (e) FISH with probes to DNA of HSV. Localization of HSV DNA in sperm heads (arrows).
Herpetic infection of spermatozoa was significantly more common in infertile men and men whose spouses had a history of spontaneous miscarriage or ART failure as compared with fertile men. Specific antiherpetic treatment of men diagnosed with HSV infection of spermatozoa results in a substantial, almost fivefold increase in the rates of blastocyst formation after ICSI and clinical pregnancy after ART [100].
Bacterial colonies were detected in ejaculate samples from patients with fertility disorders. In the colonies, heteromorphic microorganisms were held together in a diffusive substance, probably of a polysaccharide nature, or covered with membranes as bacterial biofilms. The majority of microcolonies were attached to squamous epithelial cells, whereas some were associated with sperm heads or tails (Figure 9a–d).
(a) Bacterial microcolony (B) attached to sperm head (H). (c) Bacterial microcolony (B) attached to sperm tail (T). (b, d) Bacterial microcolonies attached to the epithelial cells (EC). A diffuse substance (a–c) or membranes (Me) (d) are detected between bacterial cells.
Moretti et al. [101] examined ejaculate samples from infertile patients and detected
Bacteria may damage spermatozoa even in the absence of an overt inflammatory reaction. We observed higher contents of acrosome-reacted spermatozoa (i.e., those with a premature acrosomal reaction) in the ejaculate samples that contained bacterial microcolonies [55].
Despite the success of molecular biology, the morphological methods of research continue to play a considerable role in determining the reasons of male subfertility and infertility.
Indications for the studies using TEM are as follows:
Idiopathic infertility with normozoospermia or with small deviations in the semen parameters (revealing anomalies of spermatozoa that are not visible in the traditional spermiological study).
Examination of patients whose wives had a history of miscarriage due to abnormal embryo development, such as non-developing pregnancy or spontaneous abortion in the first trimester of natural pregnancy or ART failure.
Differential diagnosis of genetically determined and functional forms of asthenozoospermia and teratozoospermia.
Testing for ultrastructural sperm abnormalities makes it possible not only to identify the cause of infertility but also to choose proper clinical tactics, that is, to select treatments, to recommend ART using own spermatozoa, or to offer ART using donor sperm.
This work was supported by the Russian Science Foundation (project no. 14-50-00029) and the Russian Foundation for Basic Research (project no. 16-04-01447) and by Moscow State University Development Program PNR5.13.
IntechOpen publishes different types of publications
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\\n\\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\\n\\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
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\n\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
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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,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"}}}]},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"41",type:"subseries",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"