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Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty DesirĂ©e Nieuwenhuis | NatĂ lia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. 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BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including âonset of puberty and adiposity/obesityâ, âonset of pubertyâ, âchildren with obesityâ, âadipose tissueâ, âchildhood obesityâ, âadiposityâ, âobesityâ, âadipokine(s)â, âHPG axisâ, âadipokines ovary/ova- riesâ, or âadipokines testesâ, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are goverCryptocurrency regulations in Africa vary significantly across the continent, reflecting different approaches by governments to balance innovation with consumer protection and financial stability. Here's an overview of the regulatory landscape in several key African countries: 1. Nigeria Central Bank Ban: In February 2021, the Central Bank of Nigeria (CBN) banned financial institutions from providing services to crypto exchanges, effectively restricting crypto transactions through traditional banking channels. eNaira: Despite the restrictive stance on cryptocurrencies, Nigeria launched its central bank digital currency (CBDC), the eNaira, in October 2021, aiming to enhance financial inclusion and support the digital economy. 2. South Africa Regulatory Framework: The Financial Sector Conduct Authority (FSCA) has proposed a regulatory framework to classify cryptocurrencies as financial products. This will subject crypto service providers to regulations similar to those governing other financial services. AML/CFT Compliance: Crypto exchanges are required to comply with Anti-Money Laundering (AML) and Combating the Financing of Terrorism (CFT) regulations. 3. Kenya Regulatory Caution: The Central Bank of Kenya (CBK) has issued warnings about the risks associated with cryptocurrencies but has not imposed an outright ban. Cryptocurrencies are not considered legal tender. Innovation Support: Kenya is known for its innovative financial services sector, including mobile money, which creates a fertile ground for crypto and blockchain adoption despite the cautious regulatory stance. 4. Ghana Regulatory Research: The Bank of Ghana is conducting research into cryptocurrencies and blockchain technology, with a focus on understanding the potential benefits and risks. Sandbox Initiative: Ghana has introduced a regulatory sandbox to encourage innovation in fintech, including blockchain and cryptocurrencies. 5. Uganda Regulatory Oversight: The Bank of Uganda has warned the public about the risks of cryptocurrencies but has not imposed a ban. There is ongoing discussion about developing a regulatory framework. Blockchain Adoption: Uganda is exploring the use of blockchain technology in various sectors, including agriculture and healthcare. 6. Zimbabwe Ban and Reconsideration: The Reserve Bank of Zimbabwe (RBZ) initially banned banks from processing crypto transactions but has since been exploring ways to regulate the industry. Blockchain Task Force: The government has established a blockchain and digital assets task force to study the implications and potential uses of the technology. 7. Tanzania Government Support: In 2021, the Tanzanian government indicated support for adopting blockchain and cryptocurrency technologies, with the central bank working on creating a regulatory framework. Presidential Endorsement: President Samia Suluhu Hassan called on the central bank to prepare for the adoption of cryptocurrencies. Regional Initiatives and Trends Cross-Border Collaboration: Some African countries are exploring regional cooperation to harmonize crypto regulations and promote cross-border fintech solutions. Fintech Hubs: Countries like Nigeria, South Africa, and Kenya are becoming fintech hubs, attracting startups and investment in the blockchain and crypto space. Education and Awareness: Efforts are being made to educate the public and policymakers about cryptocurrencies and blockchain technology to promote informed decision-making. Challenges and Considerations Regulatory Uncertainty: The lack of clear and consistent regulations across the continent poses challenges for businesses and investors. Risk Management: Balancing innovation with risk management, particularly concerning AML/CFT compliance, is a key concern for regulators. Infrastructure and Accessibility: Limited internet access and technological infrastructure can hinder widespread adoption and effective regulation. The regulatory landscape for cryptocurrencies in Africa is dynamic and evolving, with a mix of cautious approaches and supportive measures aimed at harnessing the benefits of blockchain technology while managing associated risks.Generate exact multiple choice questions as give below 1. **Which round of negotiations led to the establishment of the World Trade Organization (WTO)?** - (a) Doha Round - (b) Tokyo Round - (c) Uruguay Round - (d) Kennedy Round **Answer:** (c) Uruguay Round 2. **The General Agreement on Tariffs and Trade (GATT) dealt with:** - (a) Goods only - (b) Services only - (c) Intellectual property only - (d) All of the above **Answer:** (a) Goods only 3. **The 'National Treatment' principle means:** - (a) Exported products are treated equally in the domestic market - (b) Imported goods are treated the same as local goods in the domestic market - (c) Exported products should have the same tariff - (d) None of the above **Answer:** (b) Imported goods are treated the same as local goods in the domestic market 4. **'Bound tariff' refers to:** - (a) A limit on tariffs for imports based on WTO commitments - (b) The tax rate on all exports - (c) The overall cost of tariffs - (d) A tariff-free trade condition **Answer:** (a) A limit on tariffs for imports based on WTO commitments 5. **The Most-Favoured Nation (MFN) principle ensures:** - (a) Equal treatment for all WTO members - (b) Only certain countries receive benefits - (c) Tariffs are raised annually - (d) One country is favored over others **Answer:** (a) Equal treatment for all WTO members 6. **The Agreement on Agriculture includes commitments in:** - (a) Market access, domestic support, and export subsidies - (b) Increasing crop yield and technology access - (c) Subsidizing imports only - (d) Agricultural tariffs only **Answer:** (a) Market access, domestic support, and export subsidies 7. **Which agreement replaced the Multi-Fiber Arrangement (MFA)?** - (a) Agreement on Textiles and Clothing - (b) Agreement on Agriculture - (c) TRIPS Agreement - (d) Technical Barriers to Trade Agreement **Answer:** (a) Agreement on Textiles and Clothing 8. **The WTO's TRIPS Agreement pertains to:** - (a) Agricultural products - (b) Intellectual property rights - (c) Investment measures - (d) Customs valuation **Answer:** (b) Intellectual property rights 9. **The Doha Round primarily focuses on:** - (a) Tariffs on manufactured goods - (b) Trade in agricultural goods - (c) Technology trade - (d) Intellectual property in medicine **Answer:** (b) Trade in agricultural goods 10. **The WTO aims to:** - (a) Restrict all trade - (b) Facilitate free and fair trade - (c) Promote monopoly - (d) Limit member negotiations **Answer:** (b) Facilitate free and fair trade 11. **RTAs aim to:** - (a) Block international trade - (b) Reduce trade barriers within a group of countries - (c) Increase tariffs among members - (d) Promote non-trade-related policies **Answer:** (b) Reduce trade barriers within a group of countries 12. **Customs unions require members to:** - (a) Keep individual external tariffs - (b) Impose the same external tariff on non-members - (c) Remove tariffs only temporarily - (d) Avoid any tariffs within the union **Answer:** (b) Impose the same external tariff on non-members 13. **The WTO's highest decision-making body is:** - (a) General Council - (b) Ministerial Conference - (c) TRIPS Council - (d) Dispute Settlement Body **Answer:** (b) Ministerial Conference 14. **Which principle prevents discrimination between WTO members?** - (a) MFN - (b) National Treatment - (c) Market Access - (d) Subsidy Reduction **Answer:** (a) MFN 15. **A common market involves:** - (a) A shared currency - (b) Free movement of goods, services, and factors of production - (c) Only trade agreements for goods - (d) No tariffs on agriculture **Answer:** (b) Free movement of goods, services, and factors of production 16. **The Agreement on Subsidies and Countervailing Measures addresses:** - (a) Trade in textiles - (b) Subsidies that distort trade - (c) All intellectual property laws - (d) Agricultural trade only **Answer:** (b) Subsidies that distort trade 17. **The WTO's TRIMs Agreement regulates:** - (a) Investments - (b) Trade in goods - (c) Trade in services - (d) Agricultural products **Answer:** (a) Investments 18. **The primary goal of the WTO's SPS Agreement is:** - (a) To allow subsidies on food exports - (b) To prevent arbitrary sanitary restrictions on trade - (c) To regulate intellectual property - (d) To impose environmental standards **Answer:** (b) To prevent arbitrary sanitary restrictions on trade 19. **A trading bloc is:** - (a) A group of countries with no trade agreements - (b) A group of countries that may have a common external tariff - (c) Only formed by countries from the same continent - (d) An agreement that restricts all trade **Answer:** (b) A group of countries that may have a common external tariff 20. **The GATT was succeeded by the WTO because:** - (a) GATT was only for developed countries - (b) WTO covers more areas like services and intellectual property - (c) GATT was non-binding - (d) WTO allows subsidies for agriculture **Answer:** (b) WTO covers more areas like services and intellectual property Certainly! Here are an additional 30 multiple-choice questions based on the document content, with answers provided after each question. --- ### Additional Questions and Answers 21. **The WTOâs Agreement on Technical Barriers to Trade (TBT) seeks to:** - (a) Restrict imports to a minimum - (b) Prevent standards from becoming unnecessary trade barriers - (c) Allow countries to set any standard for goods - (d) Promote only national standards for products **Answer:** (b) Prevent standards from becoming unnecessary trade barriers 22. **The Trade Policy Review Mechanism (TPRM) is designed to:** - (a) Impose tariffs on certain goods - (b) Regularly review and assess national trade policies - (c) Regulate customs duties globally - (d) Control intellectual property rights **Answer:** (b) Regularly review and assess national trade policies 23. **The principle of âprogressive liberalizationâ means that:** - (a) Trade barriers are reduced gradually over time - (b) All tariffs are removed immediately - (c) Only developed countries reduce trade barriers - (d) No commitments are required from developing countries **Answer:** (a) Trade barriers are reduced gradually over time 24. **Which council oversees the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS)?** - (a) General Council - (b) Services Council - (c) TRIPS Council - (d) Agriculture Council **Answer:** (c) TRIPS Council 25. **The WTOâs 'Dispute Settlement Body' is responsible for:** - (a) Deciding on national trade policies - (b) Settling trade disputes between member countries - (c) Creating new trade agreements - (d) Setting tariffs for member countries **Answer:** (b) Settling trade disputes between member countries 26. **A customs union differs from a free trade area because it:** - (a) Allows tariffs between member countries - (b) Establishes a common external tariff for non-members - (c) Applies only to services - (d) Imposes import quotas on all goods **Answer:** (b) Establishes a common external tariff for non-members 27. **Which of the following agreements deals with cross-border investments?** - (a) TRIPS - (b) TBT - (c) TRIMs - (d) GATS **Answer:** (c) TRIMs 28. **In a preferential trade agreement, member countries:** - (a) Impose the same tariffs as non-members - (b) Reduce trade barriers for each other only - (c) Apply high tariffs to non-member countries - (d) Have no external trade barriers **Answer:** (b) Reduce trade barriers for each other only 29. **The WTOâs Agreement on Agriculture includes which commitment?** - (a) Export subsidies for all agricultural goods - (b) Reduction of domestic support for farmers - (c) Complete elimination of tariffs on food products - (d) Increase in import quotas on agricultural goods **Answer:** (b) Reduction of domestic support for farmers 30. **The Agreement on Anti-Dumping allows countries to:** - (a) Increase exports by lowering prices - (b) Impose duties on imports sold below fair market value - (c) Eliminate all tariffs on certain goods - (d) Restrict domestic production of certain goods **Answer:** (b) Impose duties on imports sold below fair market value 31. **The main objective of WTOâs âNational Treatmentâ principle is to:** - (a) Prevent imports altogether - (b) Treat foreign goods the same as domestic goods - (c) Impose tariffs on all foreign products - (d) Promote exports **Answer:** (b) Treat foreign goods the same as domestic goods 32. **Which of the following is a major goal of the WTO?** - (a) Ensuring trade restrictions remain high - (b) Promoting international free trade and competition - (c) Limiting access to global markets - (d) Supporting only developed countries **Answer:** (b) Promoting international free trade and competition 33. **An economic and monetary union involves:** - (a) A free trade area only - (b) A common currency among members - (c) No external trade agreements - (d) Different currencies for each member country **Answer:** (b) A common currency among members 34. **The WTO's Ministerial Conference meets:** - (a) Annually - (b) Every two years - (c) Quarterly - (d) Every five years **Answer:** (b) Every two years 35. **The WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) mandates:** - (a) Free trade for all countries - (b) Uniform intellectual property protection standards - (c) Different IP laws for each country - (d) No IP protection for developing countries **Answer:** (b) Uniform intellectual property protection standards 36. **The WTO principle of 'transparency' requires member countries to:** - (a) Keep trade policies secret - (b) Publicly disclose trade policies and practices - (c) Have identical trade policies - (d) Eliminate tariffs on all goods **Answer:** (b) Publicly disclose trade policies and practices 37. **One of the WTO's objectives in dispute settlement is to:** - (a) Resolve trade disputes peacefully - (b) Impose sanctions on non-members - (c) Regulate global tariffs - (d) Control member states' import quotas **Answer:** (a) Resolve trade disputes peacefully 38. **Under the WTO's Market Access commitment, member countries agree to:** - (a) Allow unrestricted imports - (b) Set maximum tariff levels on imported goods - (c) Ban certain goods from other countries - (d) Only trade with specific countries **Answer:** (b) Set maximum tariff levels on imported goods 39. **GATS, or the General Agreement on Trade in Services, governs trade in:** - (a) Agricultural goods - (b) Intellectual property - (c) Services - (d) Manufactured products **Answer:** (c) Services 40. **The Agreement on Pre-shipment Inspection (PSI) aims to:** - (a) Ensure high tariffs on all imports - (b) Allow for inspection of goods before shipping - (c) Eliminate export taxes - (d) Control intellectual property trade **Answer:** (b) Allow for inspection of goods before shipping 41. **Which of the following agreements aims to harmonize customs valuation?** - (a) Anti-Dumping Agreement - (b) Customs Valuation Agreement - (c) TRIMs Agreement - (d) Agreement on Subsidies **Answer:** (b) Customs Valuation Agreement 42. **A significant aspect of the Doha Round is:** - (a) Reducing tariffs on agricultural products - (b) Restricting intellectual property rights - (c) Eliminating all forms of trade - (d) Blocking services trade agreements **Answer:** (a) Reducing tariffs on agricultural products 43. **The term âdumpingâ in international trade refers to:** - (a) Exporting goods at prices lower than domestic market prices - (b) Importing goods illegally - (c) Increasing domestic prices - (d) Imposing excessive tariffs **Answer:** (a) Exporting goods at prices lower than domestic market prices 44. **WTO members are expected to follow which key principle in reducing tariffs?** - (a) National Treatment - (b) Progressive Liberalization - (c) Quota System - (d) Non-Discrimination **Answer:** (b) Progressive Liberalization 45. **The WTO aims to promote fair competition by:** - (a) Allowing tariffs as the only form of protection - (b) Supporting MFN and anti-dumping measures - (c) Limiting access to agricultural products - (d) Increasing subsidies **Answer:** (b) Supporting MFN and anti-dumping measures 46. **A plurilateral agreement within the WTO:** - (a) Includes all WTO members - (b) Involves only specific countries with shared interests - (c) Bans all tariffs for members - (d) Imposes global trade restrictions **Answer:** (b) Involves only specific countries with shared interests 47. **Trade facilitation in the WTO context means:** - (a) Making trade faster, cheaper, and more predictable - (b) Increasing tariffs on imports - (c) Eliminating all customs procedures - (d) Restricting trade with non-members **Answer:** (a) Making trade faster, cheaperIn this video we take a look at the 0:02 fetch to code 0:03 execute cycle including its effect on 0:06 the various registers we've previously 0:12 [Music] 0:14 discussed a computer is defined Definition 0:17 as an electronic device that takes an 0:20 input 0:22 processes data 0:25 and delivers output 0:29 in this simple example you can see we're 0:31 taking the input 5 0:35 we're multiplying it by 2 that's our 0:37 process 0:39 and we're outputting 10. 0:44 but this could be way more complex for 0:46 example of a game console 0:48 the input could be the buttons you press 0:50 on a controller 0:53 the processes would then be carried out 0:55 by the console itself 0:59 and the output would be some form of 1:01 update to a monitor 1:02 and sound out for a speaker possibly 1:04 vibration feedback through the 1:06 controller 1:10 to process data a computer follows a set 1:13 of instructions 1:14 known as a computer program 1:18 if we take the lid off a typical desktop 1:20 computer we can identify 1:22 two critical components the memory 1:26 that stores the program and the central 1:29 processing unit or processor 1:31 which is under this large fan and 1:33 carries out the instructions 1:37 a computer carries out its function by 1:40 fetching 1:41 instructions decoding them and then 1:43 executing them 1:44 in a continuous repetitive cycle 1:46 billions of times a second 1:48 let's look at each of these stages in a 1:50 little more detail Fetch 1:53 so let's start with the fetch stage the 1:55 very first thing that happens 1:57 is the program counter is checked as it 2:00 holds the address 2:01 of the next instruction to be executed 2:07 the address stored is then copied into 2:09 the memory address register 2:14 the address is then sent along the 2:16 address bus to main memory 2:18 where it waits to receive a signal from 2:21 the control 2:22 bus so it knows what to do 2:27 as we want to read the data that's 2:29 stored in memory address 2:30 0 0 0 0 the control unit sends 2:34 a read signal along the control bus to 2:36 main memory 2:41 now main memory knows the data needs to 2:44 be read 2:45 the content stored in memory address 000 2:49 can be sent along the data bus to the 2:51 memory data register 2:56 now as we're currently in the process of 2:58 fetching an instruction 3:00 the data received by the memory data 3:03 register gets copied 3:04 into the current instruction register 3:11 the instruction effectively has now been 3:14 fetched from memory 3:16 just before we proceed to the decode 3:18 phase we now 3:19 increment the program counter so that 3:22 the address it contains 3:24 points to the address of the next 3:26 instruction which will need to be 3:30 executed 3:32 the instruction now being held in the 3:33 current instruction register 3:35 is ready to be decoded 3:39 now as we mentioned in the previous 3:41 video the instruction is made up of two 3:43 parts 3:44 we have the op code that's what it is we 3:47 need to do 3:50 and we have the operand what are we 3:53 going to do it to 3:55 now the operand could contain the actual 3:57 data 3:58 or indeed it could contain an address of 4:01 where the data is to be found 4:06 by decoding this instruction we can see 4:08 the operation we need 4:10 is a load operation so we need to load 4:14 the contents of memory location0101 4:18 into the cpus accumulator 4:25 in the exam a simple model will be used 4:27 to describe the 4:29 structure of any given instruction 4:32 you're not going to be expected to 4:34 define how an opcode is made up 4:36 but simply to interpret opcodes in the 4:39 given context of an exam 4:40 question in the example here 4:44 you can see there's a total of 16 4:46 different opcodes available 4:48 and this is because we're using four 4:50 bits for our representation 4:56 so now we've fetched the instruction and 4:59 we've decoded it so we know what we need 5:00 to do 5:01 we're finally ready to execute it 5:05 so we now send address 0101 5:08 to the memory dress register 5:13 now we're in the memory address register 5:15 we can finally send the address 5:18 down the address bus to main memory 5:24 this time we want to read the data 5:26 that's stored in memory 5:28 and so the control unit again sends a 5:30 read signal along the control bus 5:36 so main memories now receive an address 5:38 and a read signal 5:40 so the content stored at memory location 5:43 0101 5:44 can now be sent along the data bus back 5:46 to the cpu 5:47 and into the memory data register 5:54 finally the contents of the memory data 5:56 register are copied to the accumulator 5:59 and this is one of a number of general 6:00 purpose registers found in the cpu 6:04 this first instruction is now complete Branching 6:11 so what does this program actually do 6:14 you should be able to work it through 6:16 carefully and figure it out 6:19 we're now pointing instructions zero 6:21 zero zero one in the program counter 6:23 and we're ready to fetch the second 6:25 instruction 6:27 at the end of this video we're gonna 6:29 provide you with the answer 6:34 so let's talk a second about programs 6:37 that branch 6:40 on the left here we have a very simple 6:42 piece of pseudo code 6:44 line zero says first execute this line 6:46 of code 6:47 line 1 now execute this line and then 6:50 line 2 says 6:52 if the age is greater than 18 then 6:56 we're going to execute lines 3 and 4 6:58 otherwise 6:59 we're going to execute lines six and 7:02 seven 7:03 so this program doesn't necessarily 7:05 follow strictly in sequence from line 7:07 zero through to seven there's a chance 7:10 here the program may branch and jump 7:14 around 7:16 so we're going to pretend that this 7:17 program has been loaded into memory 7:20 each line of code on the left here has 7:23 ended up 7:24 as a location in memory now this is not 7:27 strictly how this would happen in this 7:28 one-to-one way 7:29 but for the purpose of example it's 7:31 absolutely fine 7:35 so the program counter starts by 7:37 pointing to memory address zero 7:39 and we fetch the first instruction 7:41 decode it and execute it 7:44 it then updates and tells us the next 7:47 instruction 7:48 is zero zero zero one because remember 7:50 the program counter is being incremented 7:52 so we fetch it decode it and we execute 7:55 line one of our program 7:59 we then fetch line two which in binary 8:01 is one 8:02 zero 8:06 now at this point depending on what 8:10 happens during the execution 8:11 of line two the program may be required 8:15 to fetch line three from memory or 8:18 line five from memory 8:25 so let's look at how this actually works 8:27 because we've said the program counter 8:28 simply gets incremented 8:31 well in the current instruction register 8:33 we have an instruction with the op code 8:36 0 1 1 0. 8:41 now when we look this up in the decode 8:43 unit we discover that this 8:45 code means branch always 8:51 this replaces the value held in the 8:54 program counter 8:56 with the contents of the operand that's 8:58 the second part of the instruction 9:01 from the current instruction register so 9:03 this case 9:04 one zero zero one 9:09 now when the next fetch cycle begins the 9:12 program counter is obviously checked 9:14 and as its contents have been previously 9:16 updated to a new memory location 9:19 and not simply incremented the program 9:22 effectively is able to jump 9:24 around memory 9:28 so having watched this video you should 9:30 be able to answer the following key 9:32 question 9:33 how does a cpu work 9:39 okay so let's um answer the question we 9:41 posed 9:42 earlier what did that program actually 9:48 do 9:50 so this is the first fetch to code 9:53 execute cycle 9:55 and this is the one that we ran through 9:57 in detail earlier 9:58 it effectively loaded the contents of 10:01 the memory 10:02 stored at location location0101 10:05 into the accumulator in other words 10:08 the dna number 3 is moved 10:11 from memory into the cpu 10:18 we then proceed onto the second fetch 10:20 decode execute cycle 10:23 now this one adds the contents of memory 10:27 located at 0 1 1 0 10:30 to the current contents of the 10:32 accumulator 10:34 so in other words the dna number one 10:38 because that's what's stored at address 10:40 zero one one zero 10:43 is added to the number three that was in 10:45 the accumulator 10:46 the results are stored back over the 10:48 accumulator 10:49 so effectively we've done three plus one 10:53 equals four 10:58 the third fetch to code execute cycle 11:00 stores the contents which are in the 11:02 accumulator 11:03 into memory location zero one one one 11:07 and that's because the op code the first 11:09 part of this current instruction 11:10 zero zero one one is the command to 11:13 store when we look it up in the decoder 11:15 unit 11:16 so in other words the result of the 11:17 previous calculation three plus one 11:19 equals four 11:20 is now written back into main memory 11:28 the fourth fetch decode execute cycle 11:30 outputs the contents of the accumulator 11:33 remember they were copied into main 11:34 memory but they're still held in the 11:35 accumulator 11:37 so in this simple abstraction the number 11:40 four is now 11:41 output to the user so they can see the 11:43 result of the calculation 11:49 the fifth and final fetch code execute 11:51 cycle 11:52 brings a halt to the current program 11:58 so this very simple program which has 12:01 five 12:02 fetch decode execute cycles has 12:04 performed the calculation 12:06 three plus one is then stored the result 12:09 in main memory 12:10 and displayed the result four to the 12:12 user 12:13 and in a high-level language this may 12:15 look something very similar to the 12:17 following two lines of code 12:20 sum variable equals num1 plus num2 12:24 print sum to the user 12:27 so you can start to get an appreciation 12:29 here of how the high level code you 12:32 write actually ends up being fetched 12:34 decoded 12:35 and executed inside a processor 12:38 of course your processor is doing 12:40 billions and billions of these 12:42 operations a second 12:43 which when you think about it is really 12:45 very impressive 12:52 [Music] 13:03 you. make 10 questions for a standerd of a levelSome substances, such as macromolecules and nutrients, are too large to pass through the cell membrane by the transport processes you have studied so far. Cells employ two other transport mecha- nismsâendocytosis and exocytosisâto move such substances into or out of cells. Endocytosis and exocytosis are also used to transport large quantities of small molecules into or out of cells at a single time. Both endocytosis and exocytosis require cells to expend energy. Therefore, they are types of active transport. Endocytosis Endocytosis (EN-doh-sie-TOH-sis) is the process by which cells ingest external fluid, macromolecules, and large particles, including other cells. As you can see in Figure 5-7, these external materials are enclosed by a portion of the cellâs membrane, which folds into itself and forms a pouch. The pouch then pinches off from the cell membrane and becomes a membrane-bound organelle called a vesicle. Some of the vesicles fuse with lysosomes, and their con- tents are digested by lysosomal enzymes. Other vesicles that form during endocytosis fuse with other membrane-bound organelles. Two main types of endocytosis are based on the kind of material that is taken into the cell: pinocytosis (PIEN-oh-sie-TOH-sis) involves the transport of solutes or fluids, and phagocytosis (FAG-oh-sie-TOH-sis) is the movement of large particles or whole cells. Many unicellular organisms feed by phagocytosis. In addition, certain cells in animals use phagocytosis to ingest bacteria and viruses that invade the body. These cells, known as phagocytes, allow lysosomes to fuse with the vesicles that contain the ingested bacteria and viruses. Lysosomal enzymes then destroy the bacteria and viruses before they can harm the animal. CYTOSOL EXTERNAL ENVIRONMENT During endocytosis, the cell membrane folds around food or liquid and forms a small pouch. The pouch then pinches off from the cell membrane to become a vesicle. FIGURE 5-7 vesicle from the Latin vesicula, meaning âbladderâ or âsacâ Word Roots and Origins www.scilinks.org Topic: Endocytosis Keyword: HM60505 mb06se_homs02.qxd 5/18/07 11:03 AM Page 105 106 CHAPTER 5 1. Explain the difference between passive trans- port and active transport. 2. What functions do carrier proteins perform in active transport? 3. What provides the energy that drives the sodium-potassium pump? 4. Explain the difference between pinocytosis and phagocytosis. 5. Describe the steps involved in exocytosis. 6. How do endocytosis and exocytosis differ? How can that difference be seen? CRITICAL THINKING 7. Analyzing Information During intense exercise, potassium tends to accumulate in the fluid surrounding muscle cells. What membrane protein helps muscle cells counteract this tendency? Explain your answer. 8. Evaluating Differences How does the sodium- potassium pump differ from facilitated diffusion? 9. Relating Concepts The vesicles formed during pinocytosis are much smaller than those formed during phagocytosis. Explain. SECTION 2 REVIEW Vesicle Cell membrane EXTERNAL ENVIRONMENT CYTOSOL During exocytosis, a vesicle moves to the cell membrane, fuses with it, and then releases its contents to the outside of the cell. FIGURE 5-8 INSIDE OF CELL Vesicle OUTSIDE OF CELL Exocytosis Exocytosis (EK-soh-sie-TOH-sis) is the process by which a substance is released from the cell through a vesicle that transports the sub- stance to the cell surface and then fuses with the membrane to let the substance out of the cell. This process, illustrated in Figure 5-8, is basically the reverse of endocytosis. During exocytosis, vesi- cles release their contents into the cellâs external environment. Figure 5-8 also shows a photo of a vesicle during exocytosis. Cells may use exocytosis to release large molecules such as pro- teins, waste products, or toxins that would damage the cell if they were released within the cytosol. Recall that proteins are made on ribosomes and packaged into vesicles by the Golgi apparatus. The vesicles then move to the cell membrane and fuse with it, deliver- ing the proteins outside the cell. Cells in the nervous and endocrine systems also use exocytosis to release small molecules that control the activities of other cells.1. Battle of Lexington At the Battle of Lexington in 1775, British soldiers and colonial militia faced each other on the village green. A shot was fired, but no one knows for sure who fired first. Even so, this moment is often called the beginning of the American Revolution. Why is the Battle of Lexington still considered the start of the American Revolution, even though it is unclear who fired the first shot? A. It marked the first time colonists and British soldiers fought in open battle B. It proved that colonists planned the war long before the fighting began C. It showed that British soldiers were fully responsible for starting the war D. It confirmed that colonists had already declared independence from Britain 2. Battle of Concord After the fighting at Lexington, British troops marched to Concord to destroy colonial supplies. Instead, colonial militia gathered and fought back, forcing the British to retreat toward Boston. Why is the Battle of Concord considered an important turning point in the early American Revolution? A. It showed that colonial militias could organize and successfully push back British troops B. It proved that the British army had already lost control of all the colonies C. It confirmed that the colonies had officially declared independence from Britain D. It demonstrated that foreign countries were already helping the colonial forces 3. Second Continental Congress Much of the early violent conflict between colonists and British soldiers took place in Boston. After fighting broke out at Lexington and Concord near Boston, colonial leaders met at the Second Continental Congress in 1775 to decide what to do next. Which answer best describes the main actions taken by the Second Continental Congress? A. They created an army, chose a leader, and tried to avoid war with Britain B. They declared independence, wrote the Constitution, and ended the war C. They raised taxes, formed a monarchy, and supported British rule D. They ended slavery, gave women rights, and expanded voting laws 4. Olive Branch Petition In 1775, colonial leaders sent a letter called the Olive Branch Petition to King George III of Britain. Based on this situation, what was the main purpose of the Olive Branch Petition sent to the king? A. To ask the king to restore peace between both sides B. To declare independence from Britain and begin a new nation C. To request help from foreign countries in the war effort D. To organize protests against British taxes across the colonies 5. Battle of Bunker Hill On June 17, 1775, during the Battle of Bunker Hill in Boston, colonial forces fought against the British on a hill overlooking the city. The fighting was intense and led to heavy losses on both sides. Which statement best explains why the Battle of Bunker Hill was an important battle in the war? A. The colonists won the battle, showing they were stronger than British forces B. The colonists won the battle, showing the British that the war would be short and easy for the colonists C. The British won the battle, showing the war would be difficult and costly for both sides D. The British won the battle, showing British forces could defeat the colonists easily 6. Pamphlets During the American Revolution, pamphlets were short printed writings that were inexpensive to produce and often written in everyday language so many colonists could read them. How did these features of pamphlets most affect their role in the American Revolution? A. They helped spread ideas widely, allowing more colonists to form and share opinions B. They limited ideas to educated leaders, keeping most colonists uninvolved C. They replaced newspapers entirely, becoming the only source of information D. They prevented disagreement, causing most colonists to think the same way 7. Thomas Paineâs Common Sense In 1776, Thomas Paine published Common Sense, a widely read piece of writing about the relationship between the colonies and Britain. How did this pamphlet most influence colonial thinking during the American Revolution? A. It encouraged colonists to support independence from Britain B. It convinced colonists to remain loyal to the British government C. It explained how colonial armies should organize attacks D. It described laws colonists were expected to follow 8. Declaration of Independence In July 1776, the Declaration of Independence listed complaints against King George III and explained the colonistsâ ideas about government and rights. How do these parts of the Declaration of Independence work together to support the colonistsâ decision? A. They connect ideas about rights to real examples, justifying separation from Britain B. They describe past events in detail, showing how the war had already ended C. They list future plans for government, explaining how leaders would be chosen D. They organize military actions, showing how the colonies planned to win 9. Washington Crosses the Delaware and Battle of Trenton In December 1776, George Washington led his army across the Delaware River and launched a surprise attack on Hessian mercenaries in Trenton. Which statement best explains why Washingtonâs crossing of the Delaware and the attack on Trenton was an important turning point in the war? A. It defeated British forces completely, ending the war in a short time B. It boosted morale, helping discouraged soldiers choose to keep fighting C. It brought foreign allies into the war, adding support for the colonies D. It led to independence, allowing the colonies to form a new nation 10. Battle of Saratoga In 1777, American forces defeated the British at the Battle of Saratoga, a major event during the American Revolution. Which statement best explains why the Battle of Saratoga was an important turning point in the war? A. It brought French support, helping Americans gain a strong advantage in the war B. It ended the war quickly, forcing Britain to surrender all control in the colonies C. It improved army training, helping soldiers become more skilled in future battles D. It changed leadership roles, causing new generals to take control of the army 11. Battle of Yorktown In 1781, American forces surrounded British troops at Yorktown, leading to a major moment in the American Revolution. Which statement best explains why the Battle of Yorktown was an important event in the war? A. French forces helped the Americans win, leading to the end of major fighting in the war B. Italian forces helped the British win, leading to a final victory over the American army C. German forces switched sides and helped the Americans win, leading to a final defeat for British troops D. French forces helped the British win, leading to a complete end of the war in the colonies 12. Treaty of Paris After the Battle of Yorktown, British public opinion turned against the war, and peace negotiations began. In 1783, American leaders signed the Treaty of Paris, which included agreements between the United States and Britain. Which statement best explains how the Treaty of Paris reflected the outcome of the American Revolution? A. Both sides made agreements, recognizing independence B. Americans gained independence, taking land without agreements C. British leaders kept control, ending the war with power D. Both sides refused compromise, continuing the warName of the 7 continents and popular things 7 continents