\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\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:"6588",leadTitle:null,fullTitle:"Plasmid",title:"Plasmid",subtitle:null,reviewType:"peer-reviewed",abstract:"This book captures in a single volume the wealth of information on the plasmid structure, function, and biology of all organisms that have been examined to date. Plasmids exhibit wide variations in size, modes of replication and transmission, host ranges, and the genes they carry and have provided us with a great understanding of basic life principles at the molecular level. Written by experts in the field, this book is a valuable source of up-to-date information, delivering the latest impacts on studies in the areas of plasmid types, genomes, purification analysis, and expression of recombinant proteins in bacteria. Plasmid utilization in the synthesis of plasmid-based vaccines, plasmids as genetic tools, and their applications in ecology and the evolutionary process are also covered. This book is a single source of valuable information for instructors and students in advanced undergraduate and graduate courses on plasmids. It will also appeal to researchers seeking to find new relationships between biological processes that are linked by plasmids to the environment.",isbn:"978-1-83880-238-7",printIsbn:"978-1-83880-237-0",pdfIsbn:"978-1-83881-126-6",doi:"10.5772/intechopen.71424",price:100,priceEur:109,priceUsd:129,slug:"plasmid",numberOfPages:70,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"7411c33be05d3ce296d294c3c01af404",bookSignature:"Munazza Gull",publishedDate:"June 19th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/6588.jpg",numberOfDownloads:10127,numberOfWosCitations:4,numberOfCrossrefCitations:3,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:14,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:21,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 13th 2017",dateEndSecondStepPublish:"January 10th 2018",dateEndThirdStepPublish:"March 4th 2018",dateEndFourthStepPublish:"May 23rd 2018",dateEndFifthStepPublish:"July 22nd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"186160",title:"Prof.",name:"Munazza",middleName:null,surname:"Gull",slug:"munazza-gull",fullName:"Munazza Gull",profilePictureURL:"https://mts.intechopen.com/storage/users/186160/images/6128_n.jpg",biography:"Dr. Munazza Gull is currently working as Associate Professor, in Biochemistry Department, Faculty of Science, King Abdul Aziz University, Jeddah, Kingdom of Saudi Arabia. She graduated (MSc. Plant Sciences) from University of Agriculture, Faisalabad, Pakistan in 1999. She received her M.Phil degree from the same university Plant Sciences Microbiology in 2002. She obtained her PhD in Biotechnology in 2008 and also worked as researcher from National Institute of Biotechnology and Genetic Engineering, Faisalabad ,Pakistan (NIBGE) /Quaid i-Azam University Islamabad, Pakistan. She has experience in Microbial biotechnology and genetics and is active in the following subjects: Biotechnology and sustainable Environment, Microbe-interactions, biopreparates/biostimulators/bioproducts studies. She previously worked with rhizobacteria, Biocontrol, Integrated disease management, Secondary metabolites/bioproducts/antimicrobial bioactive compounds. 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Based on these backgrounds, the technique to purify plasmid DNA has been discussed.",signatures:"Noboru Sasagawa",downloadPdfUrl:"/chapter/pdf-download/60894",previewPdfUrl:"/chapter/pdf-preview/60894",authors:[{id:"240378",title:"Prof.",name:"Noboru",surname:"Sasagawa",slug:"noboru-sasagawa",fullName:"Noboru Sasagawa"}],corrections:null},{id:"65632",title:"Plasmids for Optimizing Expression of Recombinant Proteins in E. coli",doi:"10.5772/intechopen.82205",slug:"plasmids-for-optimizing-expression-of-recombinant-proteins-in-em-e-coli-em-",totalDownloads:1830,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Plasmids are important vectors for the transfer of genetic material among microbes. The transfer of plasmids causes transmission of genes involved in pathogenesis and survival, to the host bacteria leading to their evolution and adaptation to diverse environmental conditions. A large number of plasmids of varying sizes have been discovered and isolated from various microorganisms. Plasmids are also valuable tools to genetically manipulate microbes for various purposes including production of recombinant proteins. Escherichia coli is the most preferred microbe for production of recombinant proteins, due to rapid growth rate, cost-effectiveness, high yield of the recombinant proteins and easy scale-up process. Several plasmids have been designed to optimize the expression of heterologous proteins in E. coli. In order to circumvent the issues of protein refolding, the codon usage in E. coli, the absence of post-translational modifications, such as glycosylation and low recovery of functionally active recombinant proteins, various plasmids have been designed and constructed. 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White",authors:[{id:"105297",title:"Mr.",name:"Brett",middleName:null,surname:"Wedding",fullName:"Brett Wedding",slug:"brett-wedding"}]},{id:"36051",title:"Time-Resolved FTIR Difference Spectroscopy Reveals the Structure and Dynamics of Carotenoid and Chlorophyll Triplets in Photosynthetic Light-Harvesting Complexes",slug:"time-resolved-ftir-difference-spectroscopy-reveals-the-structure-and-dynamics-of-carotenoid-and-chlo",signatures:"Alexandre Maxime and Rienk van Grondelle",authors:[{id:"107363",title:"Prof.",name:"Rienk",middleName:null,surname:"Van Grondelle",fullName:"Rienk Van Grondelle",slug:"rienk-van-grondelle"}]},{id:"36052",title:"The Role of β-Antagonists on the Structure of Human Bone - A Spectroscopic Study",slug:"the-role-of-antagonists-on-the-structure-of-human-bone-a-spectroscopic-study",signatures:"J. Anastassopoulou, P. Kolovou, P. Papagelopoulos and T. 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This energy is mainly provided by sugar, carbohydrates and fat. To utilize these nutritive substances and to produce energy in return, inspired oxygen (O2) from the air is needed. In the mitochondrial electron transport chain, O2 is the final electron acceptor to generate ATP within the eukaryotic cells [1]. Whilst O2 is needed for most life on earth, most of the earth’s atmosphere does not contain a lot of O2. From the surface of the planet, up to the border of space, the atmosphere contains a constant fraction of around 21% O2 (often expressed as the FiO2 of around 0.21), 78% of nitrogen, 0.9% argon and 0.1% of other gases like carbon dioxide, methane, water vapor, etc. At sea level, the partial pressure of the above-mentioned gases can be estimated to be 593 mmHg for nitrogen, 160 mmHg for oxygen and 7.6 mmHg for argon. Indeed, the weight of air is responsible for atmospheric pressure.
It’s well known that increasing altitude leads to quasi-exponential reductions in barometric pressure (PB). At the summit of Mt. Everest (8848 m), the PB is about one-third of the sea-level values. The reduced atmospheric pressure has therefore a direct influence on the partial pressure of inspired oxygen, which can be seen in Figure 1.
Relationship between barometric pressure (PB), partial pressure of inspired oxygen (PiO2) and altitude. PB and PiO2 decrease exponentially with increasing altitude at a constant FiO2 of 21%. The solid line represents PB and the broken line represents PiO2.
The inspired partial pressure of oxygen (PiO2) is lower than atmospheric oxygen partial pressure because water vapor is in the airways. The pressure of water vapor (PH2O), which is not dependent on atmospheric pressure but temperature, should be taken into account when PiO2 is calculated [2]. The inhaled air gases will get humified and warmed by the airways and as a result, the PH2O will adjust the partial pressure of all inhaled gases, including O2.
Accordingly, the product of PiO2 can be calculated using Eq. (1):
Since PB is known to be approximately 760 mmHg at sea level, PH2O is normally about 47 mmHg and O2 makes up to 20.93% (FiO2 of 0.2093), PiO2 is equal to 0.20932 multiplied by 713 mmHg.
Consequently, hypoxia is defined as a combination of PB and the FiO2 that results in any PiO2 under a normoxic value of 150 mmHg [3]. However, the duration of hypoxic exposures as well as the magnitude of PB reductions has a significant impact on the (patho-)physiological response. Examples of fast-changing normoxic to hypoxic environments are fast ascended on the mountain summits during mountaineering, military and rescue services and travels with fast transportation to altitude. Acute mountain sickness is well-known to occur due to extensive and fast decreases in Pb, normally beginning at an altitude of above 2500 m. The Lake Louis Consensus Group defined acute mountain sickness as the presence of headache in an unacclimatised person (recently arriving at an altitude above 2500 m), plus the presence of one or more of the following symptoms: gastrointestinal symptoms, fatigue and/or weakness, dizziness or a positive clinical functional score, resulting in a total score of ≥3 [4]. If not treated correctly, people with acute mountain sickness can develop high-altitude pulmonary oedema or high-altitude cerebral oedema [5]. However, if the human body is gradually exposed to hypoxic conditions, it can acclimatize and adapt.
The following chapters will focus on the main types of hypoxia, the physiological consequences of acute hypoxia and the clinical consequences of the current chapter.
Insufficient O2 supply to the human tissues can have various reasons and can lead to severely impaired body functions. There are four main types of hypoxia, which can be classified as hypoxaemic hypoxia, anemic hypoxia, stagnant hypoxia and histotoxic hypoxia.
One of the most common types of hypoxia is called generalized or hypoxic hypoxia, which is generated from the actual (natural/simulated) environment and inside the lungs. This type is caused by a reduction of the partial pressure of alveolar O2 (PAO2) [6]. This value is well known and a great help to calculate the partial pressure of oxygen inside the alveoli (as it is not possible to collect gases directly from the alveoli), which can be used for potential cell diffusion [7]. The alveolar gas equation uses three variables to calculate the alveolar concentration of oxygen, which can be seen in Eq. (2):
where PaCO2 is the partial pressure of carbon dioxide which is under normal physiological conditions approximately 40 mmHg. RQ is the respiratory quotient which is, the ratio of the volume of produced CO2 divided by the volume of consumed O2 during the same time [8]. Dependent on metabolic activity and diet, RQ is considered to be around 0.825 [9], within a physiological range between 0.70 and 1.00. Consequently, PAO2 at sea level is: 0.2093 × (760–47) – 40/0.825 = 100.7 mmHg. PAO2 is the main driving factor for alveolar diffusion and thus O2 supply on a cellular level.
Hypoxic hypoxia can be observed typically when FiO2 is low, during hypoventilation of the lungs or at the presence of pathological airway conditions. Low FiO2 levels can occur due to failure of gas delivery systems, inadequate supply from altitude simulating machines, or e.g., exorbitant inhalation of nitrous oxide during anesthesia [10]. Hypoventilation can occur due to insufficient respiratory rate, obstruction of airways, skeletal deformities, respiratory muscle paralysis, etc. Severe lung diseases (e.g., pulmonary fibrosis, pulmonary embolism) can also lead to alveolar-capillary diffusion blockade [11]. Hypoxic hypoxia affects the entire body. Typical symptoms are agitation and anxiety while low blood O2 goes along with increased heart rate, dyspnea and bluish color of the skin.
Anemic hypoxia is caused by reduced oxygen transport capacity in the blood [12]. The red blood cells (erythrocytes) are responsible for the transport of O2 through the body [13]. Around 90% of the erythrocyte is made up of haemoglobin, the iron-containing protein that binds O2 on its heme. Although, the arterial oxygen tension is normal at this type, reduced erythrocytes/haemoglobin or functional insufficiency of haemoglobin leads to impaired oxygen delivery to the tissues [14].
A deficiency in the number of erythrocytes can result, for example, from excessive blood loss after trauma. Other forms of the reduced number of erythrocytes can be present in case of abnormal red blood cell breakdown (haemolytic anemia) [15]. Increased haemolysis can be observed during hereditary spherocytosis, sickle cell disease or autoimmune diseases (e.g., aplastic anemia) [16].
Deficiencies of different factors can also lead to severe anemia. Iron is the main component of haemoglobin, giving the blood the red color and is the prime carrier of oxygen. During the physiological haemolysis, iron will be bound to the glycoprotein transferrin for transportation to the bone marrow, where it will be reused for haemoglobin synthesis. This process helps to limit an extensive loss of iron from the body. However, iron deficiency is one of the main causes of anemia, called microcytic hypochromic anemia [6]. This type of anemia can be caused by any factor which reduces the body’s iron storage, leading to small erythrocytes with reduced haemoglobin mass [17]. In contrast, deficiencies in vitamin B12 or folic acid can cause anemia due to abnormally enlarged erythrocytes and their immature precursors, called macrocytic hyperchromic anemia [18].
Functional insufficiency of haemoglobin is associated with reduced oxygen binding capacity. An example is an intoxication through excessive carbon monoxide inhalation. Compared to oxygen, carbon monoxide has a 200–300 times higher affinity to haemoglobin. After inhalation, carbon monoxide reaches the respiratory gas exchange zone and binds on haemoglobin [10]. This chemical binding process leads to the formation of carboxyhaemoglobin. Consequently, oxygen-carrying capacity is decreased which will lead to reduced oxygen transportation to the tissues and as a consequence tissue hypoxia [19]. Another possibility of functional insufficiency for the transportation of oxygen is methaemoglobinemia. Haemoglobin changes to methaemoglobin, when bivalent iron (Fe2+) is oxidized to Fe3+, which is worthless for oxygen transport [20]. Under normal circumstances, methaemoglobin reductase limits the build-up of methaemoglobin through the reduction of haemoglobin oxidation [21]. Patients with a deficiency of methaemoglobin reductase, strong oxidative stress (e.g., smoking) and medication can therefor experience very low concentrations of tissue oxygenation, demonstrating comparable symptoms as seen in hypoxic hypoxia. However, it must be mentioned, that the unfavorable conditions of low tissue O2 can be compensated better during hypoxic hypoxia than during anemic hypoxia.
Stagnant, also called ischemic or circulatory hypoxia takes place as a cause of insufficient blood supply to the tissues while the blood is normally oxygenated. Ischemic hypoxia can be observed on a central and local level [6].
Central circulatory hypoxia can often be observed in patients with cardiac manifestations. If the left ventricular output is for example decreased, blood flow to the organs is impaired [12]. This can also happen during shock or, at a local level after strong vasoconstriction (e.g., cold exposures) or venous stagnation of blood [22]. Oxygen can only be stored to the very limited amount within the human cells. Even myoglobin, binding O2 on its heme protein, has a very limited oxygen storage capacity [23]. Consequently, myoglobin is more involved in transportation than the storage of oxygen. Oxygen saturated myoglobin enables facilitated intercellular O2 transportation, because the oxygen-enriched myoglobin molecules can “move” within the cells (facilitated diffusion) which is extremely important at a low partial pressure of O2 (PO2) [24]. Although, the gas exchange rate on the alveolar level, the concentration of haemoglobin, oxygen content and tension are on a normal level, O2 extraction at the level of the capillaries will be increased [6]. This process will directly elevate the arteriovenous difference of blood O2 content leading to venous hypoxia. However, as the increased oxygen extraction is normally insufficient to supply the tissue with an adequate amount of O2, this process will lead to impaired cellular oxygen coverage and impaired functioning.
Histotoxic hypoxia or dysoxia is a state, where cells are unable to utilize oxygen effectively [12]. This is the case, when the mitochondrial terminal oxidation is disturbed while there is sufficient oxygen available in the blood. Dysoxia will therefore lead to a pathological reduction in ATP production by the mitochondria and is not preceded by hypoxaemia [6].
An example of histotoxic hypoxia is the intoxication with cyanides, which can occur from fire sources. Intravenous and inhalation of cyanide produce a more rapid onset of hypoxia than the oral or transdermal route due to the fast diffusion into the bloodstream [25]. The main effect of cyanide intoxication is related to the inhibition of oxidative phosphorylation, where oxygen is utilized for ATP production. Cyanide can reversibly bind to the enzyme cytochrome C oxidase, blocking the mitochondrial transport chain. This will cause cellular hypoxia and, as mentioned above, pathological low levels of ATP, causing metabolic acidosis and impairment of vital functions [26, 27].
Rapid ascends from sea level to altitude and sudden exposure to a hypoxic environment will immediately lead to acute physiological responses to adapt to the acute hypoxaemic situation [28]. The degree of acute hypoxic stress about time can lead to symptoms ranging from dizziness, feeling of unreality and dim visions to rapid unconsciousness [29]. Sudden exposure to the summit of Mt. Everest will for example lead to unconsciousness within 2 min. However, when the same amount of hypoxaemia is experienced over several days to weeks, one could function relatively well under these conditions. This adjustment is called acclimatization which is a complex process over time and shows great variability within individuals [29]. In the following chapters, the acute response to sudden exposure to a hypoxic environment is discussed.
The respiratory system will directly respond to the low oxygen availability in the air and is often seen as the primary defense against the hypoxic environment. Chemosensory systems will rapidly lead to increased pulmonary ventilation because of compromised O2 availability [30]. These regulatory responses can be attributed due to specialized chemoreceptors such as the carotid bodies in the arterial circulation and neuroepithelial bodies in the respiratory tract as well as the direct response of vascular smooth muscles to hypoxia [31].
Whilst hypoxia acts as a vasodilator in the systemic circulation, it has been observed, that the vessels of the pulmonary vasculature constrict under hypoxia, leading to pulmonary hypertension [32, 33]. Hypoxic vasoconstriction is intrinsic to the pulmonary vasculature smooth muscle cells and is initiated by the inhibition of K+ channels which set the membrane potential [34]. This process will lead to depolarization, activation of Ca2+ channels as a result of the electrical impulse and, as a consequence, an increase in cytosolic calcium levels and therefore constriction of the myocytes [31]. Pulmonary hypertension might help to match ventilation and perfusion within the lungs. However, pulmonary hypertension can also lead to severe pathological situations (e.g., altitude-related right heart failure).
Carotid bodies, sensitive to monitoring a drop in arterial O2 levels, and neuroepithelial bodies, detecting changes in inspired O2, respond immediately to decreased O2 supply [35]. Both respond by activating efferent chemosensory fibers to produce cardiorespiratory adjustments during hypoxic exposures [36, 37]. When low arterial PO2 is detected, the carotid body signals the central respiratory center to increase the (minute) ventilation. The increased ventilation of the respiratory tract can be primarily associated with an elevated tidal volume and an even greater elevation in respiratory rate [38]. This hypoxic ventilatory response counteracts the hypoxic environment by decreasing PACO2, increasing PAO2 and therefore improving oxygen delivery. Genetical determinants, as well as various external factors (metabolic and respiratory stimulants), lead to wide inter-individual variety of ventilatory response intensity [39]. The increased ventilatory response demonstrates that adaptive processes are taking place and a “good” ventilatory response is known to enhance acclimatization and performance and that a very low response may contribute to the formation of illness [39, 40]. However, hyperventilation will subsequently lead to hypocapnia (increased pH) known as respiratory alkalosis by reducing the amount of carbon dioxide in the alveoli [41]. This condition will cause the oxygen dissociation curve to shift to the left and to further keep respiratory ventilation high. However, hypocapnia will also counteract the central respiratory center activation and thus limit further ventilatory increases [40, 42]. On the other hand, to reduce respiratory alkalosis, more bicarbonate will be produced from the kidneys to decrease the pH toward normal levels. This means that pulmonary ventilation is driven by low arterial PO2 and limited due to hypocapnia-induced alkalosis at the same time. This becomes clear when looking into Eq. (3), defining the alveolar ventilation as follows:
VA is the alveolar ventilation, 0.863 is a constant, VCO2 is the CO2 output and PACO2 is the alveolar CO2. The ability to maintain oxygen homeostasis is essential and the physiological systems compete against each other to provide enough tissue O2 but also to maintain pH-homeostasis.
To compensate for tissue hypoxaemia, the cardiovascular system must respond to maintain body functions. This is accomplished by increasing cardiac output, which is the product of stroke volume and heart rate [43]. Consequently, an increase in one of these variables will also lead to an increased volumetric flow rate. Upon ascent to hypoxic environments, the sympathetic nervous system activation leads to an initial increase in heart rate, cardiac output and blood pressure via the release of stress hormones [40, 44]. Stroke volume remains low in the first hours which is a consequence of reduced blood plasma volume because of bicarbonate diuresis. This occurs as a result of the fluid shift from the intravascular space and the suppression of aldosterone [40]. Interestingly, the sympathetic nervous system activation remains increased even if one is well acclimatized to altitude [45]. In contrast to sympathetic activation, cardiac output decrease once a certain level of hypoxia is reached after several days [46]. After a few days, e.g., muscle tissue adapts and extracts more O2 from the circulating blood by increasing the arterial–venous oxygen difference. This reduces the demand for higher cardiac output. Reductions in stroke volume can be attributed due to decreased plasma volume as well as the above-mentioned increased pulmonary vascular resistance. From the systemic circulation perspective, the endothelial autocoids nitric oxide and prostaglandins have received more attention as they are potentially mediating hypoxic vasodilation in the vessels [47]. Hypoxic-induced vasodilation will therefor quickly increase the blood flow to O2-deprived tissues. Low PaO2 levels will increase Ca2+ concentration inside the endothelial wall which might lead to increased synthetization of vasodilating endothelial factors [48]. The smooth muscle cells of the blood vessels also have K+ ATP-channels, that are activated once the ATP/ADP quotient drops due to hypoxia. As a result of the increased conductivity of K+, the cell membrane is hyperpolarized, followed by relaxation of the vascular muscle cells and vasodilation. This is especially well evoked in coronary and vertebral vessels [49].
PAO2 is, as mentioned earlier, at sea level around 100 mmHg and will decrease at altitude. At sea level, around 96% of haemoglobin is bound to O2 which can be seen in Figure 2. The oxyhaemoglobin dissociation curve plays a crucial role in O2 transport and demonstrates the interaction between the oxygen carrying capacity of haemoglobin and changes in partial pressure of oxygen [50]. When PAO2 drops to 50 mmHg at altitude, only about 80% of haemoglobin sites are bound to O2. The sigmoidal shape of the curve minimizes an abrupt decline in oxygen-carrying capacity of the blood. Another crucial adaptive process is, that the dissociation curve will shift to the left [51]. This is mediated by respiratory alkalosis and therefore rise in blood pH. This left shift causes that at a PAO2 of 50 mmHg, instead of 80%, around 90% of haemoglobin is bound to O2. As a result, more oxygen is bound on haemoglobin and more oxygen can be unloaded to the tissues [52].
S-shaped oxyhaemoglobin dissociation curve at sea level (solid black line). The curve is shifted left due to respiratory alkalosis under acute hypoxic exposure (broken gray line).
The brain consumes around 20% of the available oxygen at rest and is very sensitive to insufficient O2 supply [53]. The ability to process large amounts of oxygen (over a relatively small tissue mass) is necessary to support the high rate of ATP production to maintain an electrically active for the continual transmission of neuronal signals [54]. From this perspective, it is clear that hypoxia can have negative effects on cognitive function [55]. From the literature, it is well known that various factors have an important influence on cognitive impairment during hypoxia, in case they occur. These include the grade of hypoxia (e.g. altitude height), ambient temperatures, performing exercise tasks, individual physiological responses and the influence of PB [56].
One of the most sensitive regions of the central nervous system is the cerebral cortex. However, acute exposure to extreme hypoxia can also cause changes within wide regions of the brain. Subtle changes in the white and gray matter were already observed during ascending Mt. Everest and K2, reducing movement control and planning [57]. Motor speed and precision are also negatively affected in altitude compared to sea level performance [58, 59]. The complexity of central execution tasks seems to play an important role when cognitive impairment is evaluated. Cognitive impairment seems to be more prominent when complex tasks must be solved rather than simple tasks [60, 61]. Indeed, altitude accidents that occur under hypoxia might be more related to poor judgment of complex situations as a consequence of hypoxic depression of cerebral function. However, also small mistakes or even small increases in reaction time [62] can also have fatal consequences.
However, the underlying mechanisms, why cognitive performance can be impaired during hypoxia are not fully understood [61]. Cerebral circulation, which is the product of arterial oxygen content and cerebral blood flow, is dependent on the net balance between hypoxic vasodilation and hypocapnia-induced vasoconstriction. It is well documented, that cerebral blood flow is increased under acute hypoxia to maintain cerebral O2-supply [54]. Cerebral blood flow increases, despite the hypocapnia, when arterial PO2 is less than 60 mmHg (altitude greater than 2800 m). Although, interindividual varieties in cerebral blood are linked to individual variations in the ventilatory response to hypoxia [63], cerebral oxygen delivery and global cerebral metabolism are well maintained under moderate hypoxia. If cerebral oxygen consumption is constant, the question arises of what causes the cognitive impairment at altitude. Cognitive changes might be related to specific neurotransmitters that are affected by mild hypoxia (e.g., serotonin, dopamine). Furthermore, alterations in blood flow and sensory displeasure, hyperhomocysteinemia and potential neuronal damage, and a decrease in catecholamine availability combined with psychological factors appear to play a key role for reduction in cognitive function during hypoxia [61]. In case cerebral tissue oxygenation is not maintained, brain injury will occur with fatal consequences [35]. Compensatory hyperventilation, tachycardia and increased cerebral blood flow can partially maintain cerebral oxygen delivery, however, if these mechanisms work inadequately, the brain will be the first organ to be compromised.
This chapter aimed to give an overview of the main hypoxia types and the main physiological consequences. Hypoxia can occur due to occupational responsibilities, recreationally but also under pathological conditions. Ascend to altitude or exposure to environments that lower the PiO2 will have direct consequences to the entire body systems, however various modulators such as PB, the severity of hypoxia, interindividual variability, health condition and others determine the physiological consequences and adaption processes. Exposing the body specifically to hypoxic environments can be used as a therapeutic tool, to increase sports performance or to achieve other goals [64]. However, it is important to precisely understand the different types of hypoxia and what consequences they have on the human body. Clinical manifestations of hypoxia underly inter-individual variations of cardiorespiratory and other physiological responses as well as the origin of hypoxia. In general, there are two major causes of hypoxia at the tissue level which are reduced blood flow to the tissues or reduced O2 content in the blood itself [65, 66]. As a result, four main types of hypoxia arise. First, hypoxaemic hypoxia, where the O2 transport to or through the alveoli is impaired [6]. Second, anemic hypoxia where the oxygen-carrying capacity is reduced due to e.g., severe blood loss, iron and folate deficiency, haemoglobin pathologies or functional insufficiency to carry O2 [10, 12, 14]. Third, stagnant hypoxia where the transport of O2 to the tissue is impaired while the blood may be sufficiently oxygenated [6]. Finally, histotoxic hypoxia exists, where the O2 is delivered to the tissues but they are unable to utilize oxygen effectively [12].
It is important to understand, how these types influence oxygen delivery to the tissues. The product of O2 content and blood flow is considered to reflect the oxygen delivery for the whole body (or to the individual organ system). As oxygen content is the sum of dissolved oxygen and that bound to haemoglobin, total oxygen delivery can be calculated according to Eq. (4):
DO2 is the O2 delivery (ml min−1); PaO2 is the partial pressure of oxygen (kPa); SaO2 is the arterial oxygen saturation in percentage; Hb is the haemoglobin content (g dl−1); 0.023 is the solubility of oxygen (in ml dl−1 kPa−1); 1.34 is Hüfner’s constant, the oxygen-carrying capacity of saturated haemoglobin (ml g−1); and blood flow (i.e., cardiac output) in dl min−1 [67]. From this equation, it can be seen that hypoxaemic hypoxia (via reduced PaO2 and SaO2), stagnant hypoxia (via reduced blood flow) and anemic hypoxia (via reduced haemoglobin content) may cause tissue hypoxia, as these three types reduce oxygen delivery. In contrast, there is no oxygen delivery deficiency in histotoxic hypoxia but rather an impairment of the tissue to use O2 [35]. Reduced oxygen tension, hypoventilation, ventilation-perfusion mismatch, right to left shunt and impaired diffusion of oxygen can all lead to hypoxia in the body [12].
The primary measurement to evaluate the hypoxic disease state is the analysis of arterial blood gas. Using this measurement, important parameters such as partial pressure of oxygen, partial pressure of carbon dioxide, acidity (pH), oxyhaemoglobin saturation and bicarbonate concentration in arterial blood can be assessed [68]. Management and treatment of persons under hypoxia should be started as soon as the evaluation has been successfully finished, and follows three categories: maintaining patent airways, increasing the oxygen content of the inspired air and improving the diffusion capacity [69, 70, 71]. Without adequate adaption processes and management, an imbalance between oxygen demand and oxygen delivery will occur leading to impaired homeostasis within the body. Therefore, healthcare practitioners (e.g., physiotherapists, sports scientists, exercise physiologists and others) should be able to understand the causes, types and consequences of hypoxia.
In this chapter, an overview is presented on the main types of hypoxia and the physiological consequences of the main systems. Hypoxaemic, anemic, stagnant and histotoxic hypoxia originate from different etiologies. Hypoxia to the tissues can be caused by any obstacle in the oxygen cascade, beginning from the O2 molecule in the atmosphere, until being the final electron acceptor within the mitochondria to generate ATP. However, the adult compensatory mechanisms to counteract the acute hypoxic state are mainly based on our ability to hyperventilate, adequately adapt the cardiovascular response and to increase oxygen uptake to provide enough tissue O2. This chapter might contribute to improving the understanding of the different types of hypoxia and to understand the physiological responses.
The author declares no conflict of interest.
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Here, we carried out a review of signalling systems involved in maturation of male germ cells and in the process that leads them to become fully fertile. In particular, we discuss the control mechanisms involved in capacitation and acrosome reaction that act at membrane level. Indeed, spermatozoa membranes play key roles in determining the achievement of fertility: they are the interface with the surrounding environment, they locate the signal transduction systems and they are active in recognizing and binding the oocyte. In addition, we discuss the effect of several compounds that could exert a negative effect on reproductive activity, by interfering with the endocrine axis, the so-called endocrine disruptors.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Nicola Bernabò, Marina Ramal Sanchez, Luca Valbonetti, Luana\nGreco, Giulia Capacchietti, Mauro Mattioli and Barbara Barboni",authors:[{id:"88710",title:"Prof.",name:"Mauro",middleName:null,surname:"Mattioli",slug:"mauro-mattioli",fullName:"Mauro Mattioli"},{id:"88713",title:"Prof.",name:"Barbara",middleName:null,surname:"Barboni",slug:"barbara-barboni",fullName:"Barbara Barboni"},{id:"90197",title:"Dr.",name:"Nicola",middleName:null,surname:"Bernabò",slug:"nicola-bernabo",fullName:"Nicola Bernabò"},{id:"199832",title:"Dr.",name:"Luca",middleName:null,surname:"Valbonetti",slug:"luca-valbonetti",fullName:"Luca Valbonetti"},{id:"199833",title:"Dr.",name:"Marina",middleName:null,surname:"Ramal Sancez",slug:"marina-ramal-sancez",fullName:"Marina Ramal Sancez"},{id:"199834",title:"Dr.",name:"Giulia",middleName:null,surname:"Capacchietti",slug:"giulia-capacchietti",fullName:"Giulia Capacchietti"}]},{id:"58819",doi:"10.5772/intechopen.71557",title:"Germ Cell Specification: The Evolution of a Recipe to Make Germ Cells",slug:"germ-cell-specification-the-evolution-of-a-recipe-to-make-germ-cells",totalDownloads:1403,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Multicellular species use gametes for their propagation. Gametes are formed from primordial germ cells (PGCs), which develop during embryogenesis. In some species, PGCs are specified by the inheritance of a RNA granule known as germ plasm. During germ cell specification, the germ plasm conveys a unique set of properties, e.g. the germ cell specific meiotic cell cycle to the PGCs. Germ plasm assembly is controlled by independently evolving organizer proteins like Oskar in Drosophila or Bucky ball in zebrafish. These organizers are intrinsically disordered proteins, which rapidly changed their amino acid sequence during evolution. A common recipe has emerged by studies on organizer proteins for animals that use germ plasm to specify their germline. Investigating the nature of these organizers might therefore provide a clue to germ cell specification in other species, which are less accessible to molecular-genetic and embryological approaches. Moreover, we might understand how the first metazoans modified their existing cellular structures from unicellular eukaryotes to ensure their reproduction.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Pritesh Krishnakumar and Roland Dosch",authors:[{id:"220901",title:"M.Sc.",name:"Pritesh",middleName:null,surname:"Krishnakumar",slug:"pritesh-krishnakumar",fullName:"Pritesh Krishnakumar"}]},{id:"58351",doi:"10.5772/intechopen.72556",title:"Germ Cell Tumors and their Association with Pregnancy",slug:"germ-cell-tumors-and-their-association-with-pregnancy",totalDownloads:1398,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"Ovarian germ cell tumors (OGCTs) comprise 20–25% of all ovarian cancers arising from germ cells of ovary. Mature teratoma (dermoid) is the only benign and commonest germ cell tumor. Only 3–5% germ cell tumors are malignant, dysgerminomas being the most common. These tumors occur in adolescents and reproductive age group. Hence, its association with pregnancy is not uncommon. They can be reliably diagnosed with ultrasound imaging. Raised levels of tumor markers in pregnancy should be interpreted with caution. Cystectomy can be done for benign germ cell tumors. However, fertility sparing surgery with surgical staging with or without adjunctive therapy is recommended for malignant germ cell tumors (MOGTs). Surgery is safe in the second trimester of pregnancy. MOGTs are quite sensitive to chemo and radiotherapy. Three to four courses of chemotherapy with bleomycin, etoposide, and platinum is recommended. Prognosis of these germ cell tumors is excellent.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Mamta Gupta and Vandana Saini",authors:[{id:"221469",title:"Dr.",name:"Mamta",middleName:null,surname:"Gupta",slug:"mamta-gupta",fullName:"Mamta Gupta"},{id:"222224",title:"Dr.",name:"Vandana",middleName:null,surname:"Saini",slug:"vandana-saini",fullName:"Vandana Saini"}]},{id:"57528",doi:"10.5772/intechopen.71559",title:"Challenging the Paradigms on the Origin, Specification and Development of the Female Germ Line in Placental Mammals",slug:"challenging-the-paradigms-on-the-origin-specification-and-development-of-the-female-germ-line-in-pla",totalDownloads:1209,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Most of our understanding on the origin, specification and development of the female germ line in placental mammals comes from studies in the laboratory mouse. The molecular pathway leading to the development and establishment of the female germ line in mouse has erected as the paradigm for placental mammals. It remains, however, largely unexplored whether the well-established mouse regulatory pathway is a common mechanism to other or all placental mammals. Discrete differences in mammals other than mouse reveal the existence of alternative mechanisms that challenge the currently accepted tenets on the origin and establishment of the mammalian female germinal reserve. Here, we will discuss the mouse framework in the light of emerging discrepancies seen in other placental mammals.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Noelia P. Leopardo, Pablo I.F. Inserra and Alfredo D. Vitullo",authors:[{id:"214484",title:"Dr.",name:"Alfredo",middleName:"Daniel",surname:"Vitullo",slug:"alfredo-vitullo",fullName:"Alfredo Vitullo"},{id:"214485",title:"Dr.",name:"Noelia",middleName:null,surname:"Leopardo",slug:"noelia-leopardo",fullName:"Noelia Leopardo"},{id:"214486",title:"Dr.",name:"Pablo",middleName:"Ignacio Felipe",surname:"Inserra",slug:"pablo-inserra",fullName:"Pablo Inserra"}]},{id:"56303",doi:"10.5772/intechopen.69963",title:"The Regulation of Germline Stem Cells and Their Neighbouring Somatic Cells in the Fruit Fly (Drosophila melanogaster)",slug:"the-regulation-of-germline-stem-cells-and-their-neighbouring-somatic-cells-in-the-fruit-fly-drosophi",totalDownloads:1337,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The Drosophila germline stem cells (GSCs) remain as one of the most well-understood adult stem cells. The number of stem cells that self-renews and differentiates must be tightly controlled to maintain tissue homeostasis. The Drosophila GSCs are maintained by local signals emanated from the niche, which is composed of the surrounding somatic cells. Notably, GSC homeostasis is also known to be influenced by systemic signals and external stimuli. The Drosophila hormone ecdysone and its signalling cascade were found to regulate GSC homeostasis. The insulin signalling pathway as well as nutrient availability can also regulate GSC number. Furthermore, neuronal sex peptide signalling induced in female flies after mating was shown to increase GSC number. Hence, the Drosophila GSC system serves as a useful model towards understanding the mammalian stem cells. Compared with the mammalian stem cell models, the Drosophila GSC system is anatomically simpler where stem cells can be easily identified, imaged and manipulated genetically. Nevertheless, recent findings have facilitated our understanding into how GSCs and their neighbouring somatic cells sense and respond to changes in a variety of local, systemic and external stimuli.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Sharon Wui Sing Tan, Yu Cai and Gyeong Hun Baeg",authors:[{id:"198098",title:"Prof.",name:"Gyeong Hun",middleName:null,surname:"Baeg",slug:"gyeong-hun-baeg",fullName:"Gyeong Hun Baeg"},{id:"207180",title:"MSc.",name:"Sharon Wui Sing",middleName:null,surname:"Tan",slug:"sharon-wui-sing-tan",fullName:"Sharon Wui Sing Tan"},{id:"207181",title:"Dr.",name:"Yu",middleName:null,surname:"Cai",slug:"yu-cai",fullName:"Yu Cai"}]}],mostDownloadedChaptersLast30Days:[{id:"58819",title:"Germ Cell Specification: The Evolution of a Recipe to Make Germ Cells",slug:"germ-cell-specification-the-evolution-of-a-recipe-to-make-germ-cells",totalDownloads:1403,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Multicellular species use gametes for their propagation. Gametes are formed from primordial germ cells (PGCs), which develop during embryogenesis. In some species, PGCs are specified by the inheritance of a RNA granule known as germ plasm. During germ cell specification, the germ plasm conveys a unique set of properties, e.g. the germ cell specific meiotic cell cycle to the PGCs. Germ plasm assembly is controlled by independently evolving organizer proteins like Oskar in Drosophila or Bucky ball in zebrafish. These organizers are intrinsically disordered proteins, which rapidly changed their amino acid sequence during evolution. A common recipe has emerged by studies on organizer proteins for animals that use germ plasm to specify their germline. Investigating the nature of these organizers might therefore provide a clue to germ cell specification in other species, which are less accessible to molecular-genetic and embryological approaches. Moreover, we might understand how the first metazoans modified their existing cellular structures from unicellular eukaryotes to ensure their reproduction.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Pritesh Krishnakumar and Roland Dosch",authors:[{id:"220901",title:"M.Sc.",name:"Pritesh",middleName:null,surname:"Krishnakumar",slug:"pritesh-krishnakumar",fullName:"Pritesh Krishnakumar"}]},{id:"56303",title:"The Regulation of Germline Stem Cells and Their Neighbouring Somatic Cells in the Fruit Fly (Drosophila melanogaster)",slug:"the-regulation-of-germline-stem-cells-and-their-neighbouring-somatic-cells-in-the-fruit-fly-drosophi",totalDownloads:1337,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The Drosophila germline stem cells (GSCs) remain as one of the most well-understood adult stem cells. The number of stem cells that self-renews and differentiates must be tightly controlled to maintain tissue homeostasis. The Drosophila GSCs are maintained by local signals emanated from the niche, which is composed of the surrounding somatic cells. Notably, GSC homeostasis is also known to be influenced by systemic signals and external stimuli. The Drosophila hormone ecdysone and its signalling cascade were found to regulate GSC homeostasis. The insulin signalling pathway as well as nutrient availability can also regulate GSC number. Furthermore, neuronal sex peptide signalling induced in female flies after mating was shown to increase GSC number. Hence, the Drosophila GSC system serves as a useful model towards understanding the mammalian stem cells. Compared with the mammalian stem cell models, the Drosophila GSC system is anatomically simpler where stem cells can be easily identified, imaged and manipulated genetically. Nevertheless, recent findings have facilitated our understanding into how GSCs and their neighbouring somatic cells sense and respond to changes in a variety of local, systemic and external stimuli.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Sharon Wui Sing Tan, Yu Cai and Gyeong Hun Baeg",authors:[{id:"198098",title:"Prof.",name:"Gyeong Hun",middleName:null,surname:"Baeg",slug:"gyeong-hun-baeg",fullName:"Gyeong Hun Baeg"},{id:"207180",title:"MSc.",name:"Sharon Wui Sing",middleName:null,surname:"Tan",slug:"sharon-wui-sing-tan",fullName:"Sharon Wui Sing Tan"},{id:"207181",title:"Dr.",name:"Yu",middleName:null,surname:"Cai",slug:"yu-cai",fullName:"Yu Cai"}]},{id:"56417",title:"Membrane Dynamics of Spermatozoa during Capacitation: New Insight in Germ Cells Signalling",slug:"membrane-dynamics-of-spermatozoa-during-capacitation-new-insight-in-germ-cells-signalling",totalDownloads:1314,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"The study of germline stem cells and of germline cells has deep implications for the understanding of fertility, development and cancer. Nowadays, we are experiencing the very fascinating challenge of application of –OMICS technologies to this issue, which is opening new and unexpected horizons in virtually all the branches of biology. Here, we carried out a review of signalling systems involved in maturation of male germ cells and in the process that leads them to become fully fertile. In particular, we discuss the control mechanisms involved in capacitation and acrosome reaction that act at membrane level. Indeed, spermatozoa membranes play key roles in determining the achievement of fertility: they are the interface with the surrounding environment, they locate the signal transduction systems and they are active in recognizing and binding the oocyte. In addition, we discuss the effect of several compounds that could exert a negative effect on reproductive activity, by interfering with the endocrine axis, the so-called endocrine disruptors.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Nicola Bernabò, Marina Ramal Sanchez, Luca Valbonetti, Luana\nGreco, Giulia Capacchietti, Mauro Mattioli and Barbara Barboni",authors:[{id:"88710",title:"Prof.",name:"Mauro",middleName:null,surname:"Mattioli",slug:"mauro-mattioli",fullName:"Mauro Mattioli"},{id:"88713",title:"Prof.",name:"Barbara",middleName:null,surname:"Barboni",slug:"barbara-barboni",fullName:"Barbara Barboni"},{id:"90197",title:"Dr.",name:"Nicola",middleName:null,surname:"Bernabò",slug:"nicola-bernabo",fullName:"Nicola Bernabò"},{id:"199832",title:"Dr.",name:"Luca",middleName:null,surname:"Valbonetti",slug:"luca-valbonetti",fullName:"Luca Valbonetti"},{id:"199833",title:"Dr.",name:"Marina",middleName:null,surname:"Ramal Sancez",slug:"marina-ramal-sancez",fullName:"Marina Ramal Sancez"},{id:"199834",title:"Dr.",name:"Giulia",middleName:null,surname:"Capacchietti",slug:"giulia-capacchietti",fullName:"Giulia Capacchietti"}]},{id:"56483",title:"Primordial Germ Cell Reprogramming",slug:"primordial-germ-cell-reprogramming",totalDownloads:1448,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Primordial germ cells (PGCs) are the embryonic precursors of the gametes. Thus, they are unipotent cells. However, PGCs share some common features with pluripotent stem cells. Among them, PGCs show alkaline phosphatase activity and express stage-specific embryonic antigens and pluripotency factors Lin28, Oct4, Sox2, and Nanog. Under specific conditions, they undergo spontaneous reprogramming in vivo. Moreover, they can be easily reprogrammed in vitro into pluripotent embryonic germ cells (EGCs) by culturing them in the presence of basic fibroblast growth factor or the epigenetic modulator trichostatin A. Previous work in our laboratory has also proven that hypoxia alone can reprogram PGCs into hypoxia-induced embryonic germ-like cells, which have a pluripotent phenotype but which do not show self-renewal capacity. Therefore, PGCs are an interesting model to further comprehensively understand the process of cell reprogramming. This chapter reviews various methods to achieve PGC reprogramming, as well as the molecular pathways involved. We focus on soluble factors and genetic strategies to obtain pluripotent cells from PGCs. Special emphasis will be given to factors implied in energetic metabolism, epigenetics, and cell signaling transduction, both in vitro and in vivo.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Maria P. De Miguel, Yago Alcaina and Diego Sainz de la Maza",authors:[{id:"60625",title:"BSc.",name:"Yago",middleName:null,surname:"Alcaina",slug:"yago-alcaina",fullName:"Yago Alcaina"},{id:"199960",title:"Dr.",name:"Maria P",middleName:null,surname:"De Miguel",slug:"maria-p-de-miguel",fullName:"Maria P De Miguel"},{id:"207051",title:"Dr.",name:"Diego",middleName:null,surname:"Sainz De La Maza",slug:"diego-sainz-de-la-maza",fullName:"Diego Sainz De La Maza"}]},{id:"57528",title:"Challenging the Paradigms on the Origin, Specification and Development of the Female Germ Line in Placental Mammals",slug:"challenging-the-paradigms-on-the-origin-specification-and-development-of-the-female-germ-line-in-pla",totalDownloads:1209,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Most of our understanding on the origin, specification and development of the female germ line in placental mammals comes from studies in the laboratory mouse. The molecular pathway leading to the development and establishment of the female germ line in mouse has erected as the paradigm for placental mammals. It remains, however, largely unexplored whether the well-established mouse regulatory pathway is a common mechanism to other or all placental mammals. Discrete differences in mammals other than mouse reveal the existence of alternative mechanisms that challenge the currently accepted tenets on the origin and establishment of the mammalian female germinal reserve. Here, we will discuss the mouse framework in the light of emerging discrepancies seen in other placental mammals.",book:{id:"5854",slug:"germ-cell",title:"Germ Cell",fullTitle:"Germ Cell"},signatures:"Noelia P. Leopardo, Pablo I.F. Inserra and Alfredo D. Vitullo",authors:[{id:"214484",title:"Dr.",name:"Alfredo",middleName:"Daniel",surname:"Vitullo",slug:"alfredo-vitullo",fullName:"Alfredo Vitullo"},{id:"214485",title:"Dr.",name:"Noelia",middleName:null,surname:"Leopardo",slug:"noelia-leopardo",fullName:"Noelia Leopardo"},{id:"214486",title:"Dr.",name:"Pablo",middleName:"Ignacio Felipe",surname:"Inserra",slug:"pablo-inserra",fullName:"Pablo Inserra"}]}],onlineFirstChaptersFilter:{topicId:"1403",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,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. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. 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. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,annualVolume:11413,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,annualVolume:11414,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. 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. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. 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. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:5,paginationItems:[{id:"82394",title:"Learning by Doing Active Social Learning",doi:"10.5772/intechopen.105523",signatures:"Anat Raviv",slug:"learning-by-doing-active-social-learning",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Active Learning - Research and Practice",coverURL:"https://cdn.intechopen.com/books/images_new/11481.jpg",subseries:{id:"89",title:"Education"}}},{id:"82310",title:"Knowledge of Intergenerational Contact to Combat Ageism towards Older People",doi:"10.5772/intechopen.105592",signatures:"Alice Nga Lai Kwong",slug:"knowledge-of-intergenerational-contact-to-combat-ageism-towards-older-people",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Social Aspects of Ageing - 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