Loading...
Hair Evidence & Fiber Evidence
Quiz by Lindsay Giglio
Customize this quiz to suit your class
Instantly translate to 100+ languages
Tag the questions with any skills you have. Your dashboard will track each student's mastery of each skill.
Give this quiz to my class
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. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. Dif- ferential role of adipose tissues in obesity and related metabolic and vas- cular complications. 2016;2016:1-15, 1216783. 6. Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27(1):68-83. 7. Gulyaeva O, Dempersmier J, Sul HS. Genetic and epigenetic control of adipose development. Biochimica et Biophysica Acta (BBA)â Molecular and Cell Biology of Lipids. 2019;1864:3-12. 8. Khan M, Joseph F. Adipose tissue and adipokines: the association with and application of adipokines in obesity. Forensic Sci. 2014;2014: 711-724, 328592. 9. Alotaibi MF. Physiology of puberty in boys and girls and pathological disorders affecting its onset. J Adolesc. 2019;71:63-71. 10. Cousminer DL, Stergiakouli E, Berry DJ, et al. Genome-wide associa- tion study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. Hum Mol Genet. 2014;23(16):4452-4464. 11. Ahmed ML, Ong KK, Dunger DB. Childhood obesity and the timing of puberty. Trends in endocrinology and metabolism: TEM. 2009;20(5): 237-242. 12. Biro FM, Pajak A, Wolff MS, et al. Age of menarche in a longitudinal US cohort. J Pediatr Adolesc Gynecol. 2018;31(4):339-345. 13. Currie C, Ahluwalia N, Godeau E, Nic Gabhainn S, Due P, Currie DB. Is obesity at individual and national level associated with lower age at menarche? Evidence from 34 countries in the Health Behaviour in School-aged Children Study. The Journal of adolescent health: official publication of the Society for Adolescent Medicine. 2012;50(6): 621-626. 14. De Leonibus C, Marcovecchio ML, Chiavaroli V, de Giorgis T, Chiarelli F, Mohn A. Timing of puberty and physical growth in obese children: a longitudinal study in boys and girls. Pediatr Obes. 2014; 9(4):292-299. 15. Flom JD, Cohn BA, Tehranifar P, et al. Earlier age at menarche in girls with rapid early life growth: cohort and within sibling analyses. Ann Epidemiol. 2017;27(3):187-93.e2. 16. Glass NA, Torner JC, Letuchy EM, et al. The relationship between greater prepubertal adiposity, subsequent age of maturation, and bone strength during adolescence. Journal of bone and mineral research: the official journal of the American Society for Bone and Min- eral Research. 2016;31(7):1455-1465. 17. Holmgren A, Niklasson A, Nierop AF, et al. Pubertal height gain is inversely related to peak BMI in childhood. Pediatr Res. 2017;81(3): 448-454. 18. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman- Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 2001;108(2):347-353. 19. Kelly Y, Zilanawala A, Sacker A, Hiatt R, Viner R. Early puberty in 11-year-old girls: Millennium Cohort Study findings. Arch Dis Child. 2017;102(3):232-237. 20. Lazzeri G, Tosti C, Pammolli A, et al. Overweight and lower age at menarche: evidence from the Italian HBSC cross-sectional survey. 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. Selection criteria used were English language, longitudinal or cross-sectional studies assessing the onset of puberty, including menarche, thelarche, spermarche, or voice break, combined with high BMI or obesity/adiposity, and articles assessing or reviewing adipokines and its effects on the reproductive system. 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. 9 of 10 21. Lian Q, Mao Y, Luo S, et al. Puberty timing associated with obesity and central obesity in Chinese Han girls. BMC Pediatr. 2019; 19(1):1-7. 22. Deng Y, Liang J, Zong Y, et al. Timing of spermarche and menarche among urban students in Guangzhou, China: trends from 2005 to 2012 and association with Obesity. Sci Rep. 2018;8(1):263-270. 23. Li W, Liu Q. Association of prepubertal obesity with pubertal devel- opment in Chinese girls and boys: a longitudinal study. 2018;30: e23195. 24. Mendle J, Beltz AM, Carter R, Dorn LD. Understanding puberty and its measurement: ideas for research in a new generation. Journal of research on adolescence: the official journal of the Society for Research on Adolescence. 2019;29(1):82-95. 25. Pagani S, Meazza C, Gertosio C, Bozzola E, Bozzola M. Growth hor- mone receptor gene expression in puberty. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2015;47:581-584. 26. Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4(3):254-264. 27. Aguirre RS, Eugster EA. Central precocious puberty: from genetics to treatment. Best Pract Res Clin Endocrinol Metab. 2018;32(4): 343-354. 28. Sultan C, Gaspari L, Maimoun L, Kalfa N, Paris F. Disorders of puberty. Best Pract Res Clin Obstet Gynaecol. 2018;48:62-89. 29. Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH path- way in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485-500. 30. Dahl SK, Amstalden M, Coolen L, Fitzgerald M, Lehman M. Dynorphin immunoreactive fibers contact GnRH neurons in the human hypothal- amus. Reprod Sci. 2009;16(8):781-787. 31. Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci. 2009;29(38):11859-11866. 32. Zhai L, Liu J, Zhao J, et al. Association of obesity with onset of puberty and sex hormones in chinese girls: a 4-year longitudinal study. PLoS ONE. 2015;10(8):1-12, e0134656. 33. Cizza G, Dorn LD, Lotsikas A, Sereika S, Rotenstein D, Chrousos GP. Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study. Horm Metab Res. 2001;33(3):138-143. 34. Cousminer DL, WidĂ©n E, Palmert MR. The genetics of pubertal timing in the general population: recent advances and evidence for sex-spec- ificity. Curr Opin Endocrinol Diabetes Obes. 2016;23(1):57-65. 35. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44(235):291-303. 36. Lacroix AE, Whitten R. Physiology. Treasure Island (FL): Menarche. StatPearls. StatPearls Publishing; 2018. 37. McDowell MA, Brody DJ, Hughes JP. Has Age at Menarche Chan- ged? Results from the National Health and Nutrition Examination Sur- vey (NHANES) 1999â2004. J Adolesc Health. 2007;40(3):227-231. 38. de Muinich Keizer SM, Mul D. Trends in pubertal development in Europe. Hum Reprod Update. 2001;7(3):287-291. 39. Talma H, Schönbeck Y, van Dommelen P, Bakker B, van Buuren S, Hirasing RA. Trends in menarcheal age between 1955 and 2009 in the Netherlands. PLoS ONE. 2013;8:e60056-e60056. 40. Kaplan HS, Lancaster JB. An evolutionary and ecological analysis of human fertility, mating patterns, and parental investment. Off- spring: Human fertility behavior in biodemographic perspective. 2003;1: 170-223. 41. Mitan LA. Menstrual dysfunction in anorexia nervosa. J Pediatr Adolesc Gynecol. 2004;17(2):81-85. 42. Xu H, Li P-H, Barrow TM, et al. Obesity as an effect modifier of the association between menstrual abnormalities and hypertension in young adult women: Results from Project ELEFANT. PLoS ONE. 2018; 13(11):e0207929-e0207929. 43. Tauqeer Z, Gomez G, Stanford FC. Obesity in women: insights for the clinician. J Womens Health (Larchmt). 2018;27(4):444-457. 44. de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab. 1992;75(2): 442-446. 45. Lassek W, Gaulin S. Brief communication: menarche is related to fat distribution. Am J Phys Anthropol. 2007;133(4):1147-1151. 46. Loomba-Albrecht LA, Styne DM. Effect of puberty on body composi- tion. Curr Opin Endocrinol Diabetes Obes. 2009;16:10-15. 47. Simonneaux V, Bahougne T. A multi-oscillatory circadian system times female reproduction. Front Endocrinol. 2015;6:1-15. 48. Marques P, Skorupskaite K, George JT, Anderson RA. Physiology of GNRH and gonadotropin secretion. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. Endotext.org: South Dartmouth (MA); 2000. 49. Barcellos Gemelli IF, Farias EDS, Souza OF. Age at menarche and its association with excess weight and body fat percentage in girls in the Southwestern Region of the Brazilian Amazon. J Pediatr Adolesc Gynecol. 2016;29(5):482-488. 50. Aksglaede L, Juul A, Olsen LW, Sorensen TI. Age at puberty and the emerging obesity epidemic. PLoS ONE. 2009;4:1-6, e8450. 51. Ribeiro J, Santos P, Duarte J, Mota J. Association between over- weight and early sexual maturation in Portuguese boys and girls. Ann Hum Biol. 2006;33(1):55-63. 52. Budak E, Fernandez Sanchez M, Bellver J, Cervero A, Simon C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system. Fertil Steril. 2006;85(6):1563-1581. 53. Castellano JM, Tena-Sempere M. Metabolic control of female puberty: potential therapeutic targets. Expert Opin Ther Targets. 2016; 20(10):1181-1193. 54. Venancio JC, Margatho LO, Rorato R, et al. Short-term high-fat diet increases leptin activation of CART neurons and advances puberty in female mice. Endocrinology. 2017;158(11):3929-3942. 55. l'Allemand D, Schmidt S, Rousson V, Brabant G, Gasser T, Gruters A. Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol. 2002;146(4):537-543. 56. Böttner A, Jr K, MĂŒller G, et al. Gender Differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metabol. 2004;89(8):4053- 4061. 57. Unanue N, Bazaes R, Iñiguez G, Cortes F, Avila A, Mericq V. Adre- narche in Prader-Willi syndrome appears not related to insulin sensi- tivity and serum adiponectin. Horm Res. 2007;67(3):152-158. 58. Michalakis K, Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG. The complex interaction between obesity, metabolic syndrome and repro- ductive axis: a narrative review. Metabolism: clinical and experimental. 2013;62(4):457-478. 59. Machinal-Quelin F, Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue. Endo- crine. 2002;18(2):179-184. 60. Dobrzyn K, Smolinska N, Kiezun M. Adiponectin: A new regulator of female reproductive system. Int J Endocrinol. 2018;2018:1-12, 7965071. 61. Martin LJ. Implications of adiponectin in linking metabolism to testic- ular function. Endocrine. 2014;46(1):16-28. 62. Mathew H, Castracane VD, Mantzoros C. Adipose tissue and repro- ductive health. Metabolism: clinical and experimental. 2018;86:18-32. 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 10 of 10 NIEUWENHUIS ET AL. 63. Sitticharoon C, Sukharomana M, Likitmaskul S, Churintaraphan M, Maikaew P. Corrigendum to: Increased high molecular weight adiponectin, but decreased total adiponectin and kisspeptin, in central precocious puberty compared with aged-matched prepubertal girls. Reprod Fertil Dev. 2017;29:2506-2517. 64. Das UN. Is obesity an inflammatory condition? Nutrition. 2001; 17(11-12):953-966. 65. Comninos AN, Jayasena CN, Dhillo WS. The relationship between gut and adipose hormones, and reproduction. Hum Reprod Update. 2014; 20(2):153-174. 66. Singh A, Choubey M, Bora P, Krishna A. Adiponectin and chemerin: contrary adipokines in regulating reproduction and metabolic disor- ders. Reproductive sciences (Thousand Oaks, Calif). 2018;25:1462- 1473. 67. Tsatsanis C, Dermitzaki E, Avgoustinaki P, Malliaraki N, Mytaras V, Margioris AN. The impact of adipose tissue-derived factors on the hypothalamic-pituitary-gonadal (HPG) axis. Hormones (Athens). 2015; 14:549-562. 68. Kang MJ, Oh YJ, Shim YS, Baek JW, Yang S. Hwang IT. The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty. 2018;34:627-630. 69. Lee J, Song J, Hootman JM, et al. Obesity and other modifiable fac- tors for physical inactivity measured by accelerometer in adults with knee osteoarthritis: data from the osteoarthritis initiative (OAI). Arthritis Care Res (Hoboken). 2012;53-61. 70. Bramswig J, Dubbers A. Disorders of pubertal development. Deutsches Arzteblatt international. 2009;106:295-303. quiz 04 71. Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertil- ity. Cell Mol Life Sci. 2013;70(5):841-862. 72. Riumallo J, Durnin JV. Changes in body composition in adolescent boys. Eur J Clin Nutr. 1988;42(2):107-112. 73. Siervogel RM, Demerath EW, Schubert C, et al. Puberty and body composition. Horm Res. 2003;60(Suppl 1):36-45. 74. Zhang J. Gong M. Andrologia: Review of the role of leptin in the regu- lation of male reproductive function; 2018. 75. Kauffman AS, Gottsch ML, Roa J, et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology. 2007;148(4): 1774-1783. 76. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab. 2017;15:1- 11, e44337. 77. Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab. 2010;95(1):263-270. 78. Juul A, Magnusdottir S, Scheike T, Prytz S, Skakkebaek NE. Age at voice break in Danish boys: effects of pre-pubertal body mass index and secular trend. Int J Androl. 2007;30(6):537-542. 79. Lee JM, Wasserman R, Kaciroti N, et al. Timing of puberty in overweight versus obese boys. Pediatrics. 2016;137(2):137-146, e20150164. 80. He F, Guan P, Liu Q, Crabtree D, Peng L, Wang H. The relationship between obesity and body compositions with respect to the timing of puberty in Chongqing adolescents: a cross-sectional study. BMC Pub- lic Health. 2017;17:664-673. 81. Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Expres- sion of leptin and leptin receptor in the testis of fertile and infertile patients. Andrologia. 2007;39(1):22-27. 82. Martins AD, Moreira AC, Sa R, et al. Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim Biophys Acta. 1852;2015: 1824-1832. 83. Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526(1-3):26-30. 84. Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA. Age of thelarche and menarche in contemporary US females: a cross- sectional analysis. Journal of pediatric endocrinology & metabolism: JPEM. 2014;27(1-2):47-51. 85. Herman-Giddens ME, Steffes J, Harris D, et al. Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics. 2012;130(5):e1058-e1068. 86. WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1995;854:1-452. 87. Akin I, Tolg R, Hochadel M, et al. No evidence of âobesity paradoxâ after treatment with drug-eluting stents in a routine clinical practice: results from the prospective multicenter German DES.DE (German Drug-Eluting Stent) Registry. JACC Cardiovasc Interv. 2012;5(2): 162-169. 88. Marcovecchio ML, Chiarelli F. Obesity and growth during childhood and puberty. World Rev Nutr Diet. 2013;106:135-141. How to cite this article: Nieuwenhuis D, Pujol-Gualdo N, Arnoldussen IAC, Kiliaan AJ. Adipokines: A gear shift in puberty. 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 goverHair EvidenceHair as Evidence TEST ReviewPhysical Evidence; Hair, Blood, and FingerprintsAlright, Isti â hereâs a longer and more detailed English version of the Isaac Newton text, still written at a level thatâs accessible for Grade 4 students, but rich enough in information to meet PISA literacy expectations and EF A2-level vocabulary. Iâve kept sentences short, clear, and with explanations for new concepts so itâs easier for young learners to follow, while still including both famous facts and lesser-known stories. âž» Isaac Newton: The Man Who Changed the Way We See the World A Boy from a Small Village Isaac Newton was born on January 4, 1643, in Woolsthorpe, a small village in England. His life was not easy. His father died before he was born. When he was just a few months old, his mother remarried and left him to live with his grandmother. Isaac missed his parents, but he kept himself busy by making things and exploring the world around him. As a child, Isaac liked to build models and machines. He made a small windmill that could turn with the wind. He built a water clock that told the time by dripping water into a container. He even made a sundial â a clock that tells the time by using the shadow of the sun. đĄ Did you know? The sundial marks that Isaac carved as a boy can still be seen today on the wall of his old house. âž» School and Curiosity When Newton first went to school, he was not the top student. At first, he did not pay much attention in class. But one day, another boy teased him for not being smart. Newton decided to study hard to prove him wrong. Soon, he became the best in his class. Isaac loved asking questions. He wanted to know how and why things happened. He enjoyed watching the stars at night and thinking about how the world worked. âž» The Falling Apple and Gravity One of the most famous stories about Newton is the falling apple. One afternoon, Isaac sat in his motherâs garden and saw an apple drop from a tree. This made him think: âWhy does the apple fall straight down? Why doesnât it fly up into the sky?â From this question, Newton began to think about gravity â an invisible force that pulls objects toward each other. Gravity is what keeps our feet on the ground. Itâs also what keeps the Moon moving around the Earth and the planets moving around the Sun. đĄ Fun fact: The apple did not hit Newtonâs head. Thatâs just a story people made up later to make the tale more exciting. âž» Newtonâs Three Laws of Motion Newton studied movement and wrote three important rules: 1. Objects stay still or keep moving unless something makes them change. âą Example: A ball will not roll unless you push it. 2. The bigger the push, the bigger the movement. âą Example: If you kick a ball harder, it will go faster and farther. 3. Every action has an equal and opposite reaction. âą Example: When you jump off a boat, the boat moves backward as you move forward. These three laws are still used today to understand how cars, rockets, and even roller coasters work. âž» Discoveries in Light and Color Newton also studied light. He found that white light is not just one color â it is made of many colors. He used a glass prism to split sunlight into a rainbow. This helped scientists understand how colors work. âž» Inventions and New Ideas Newton made a special telescope that used mirrors instead of lenses. This type of telescope made images of planets and stars much clearer. It is still called the Newtonian telescope today. He also worked in mathematics and helped create a new type of math called calculus, which is used to study changes and movement. âž» Strange Experiments Newton was so curious that he sometimes tested ideas on himself. Once, he put a thin needle, called a bodkin, beside his eye to see how it would change his vision. It was very dangerous, but luckily he did not go blind. đĄ Did you know? Newton also studied alchemy â an old kind of science where people tried to turn metal into gold. He never succeeded, but it showed how wide his interests were. âž» Later Life and Work At the age of 27, Newton became a professor at Cambridge University. He later worked for the Royal Mint, making sure coins were made safely and stopping people from making fake money. He was very strict, and some criminals were sent to prison because of his work. Newton never married. He spent most of his life reading, writing, and doing experiments. âž» The End of His Life Isaac Newton died in 1727 at the age of 84. He was buried in Westminster Abbey, a famous place in London where great people of Britain are honored. His work changed the world forever. Even today, scientists, engineers, and students still use Newtonâs laws and ideas. đŹ Newton once said: âIf I have seen further, it is by standing on the shoulders of giants.â This means we can make new discoveries by learning from the work of others who came before us. give 10 questions to each passage with PISA literacy standard for kid 10 years, 1. Nikola Tesla: The Man Who Dreamed of Lightning Born: July 10, 1856 Died: January 7, 1943 When Nikola Tesla was a boy in Croatia, he saw a flash of lightning and asked his mother, âCan we catch the light?â That question never left him. As he grew older, Tesla became a brilliant inventor, especially fascinated by electricity. He believed in a future where energy could be sent wirelessly through the airâlike music through the radio! Tesla invented the alternating current (AC) system, which became the foundation of modern electricity. At the time, Thomas Edison promoted direct current (DC), and the two men had a fierce competition. Many laughed at Tesla's bold ideas, but he never gave up. He dreamed of wireless communication, flying machines, and even free energy for everyone. Though he died alone and poor, today the world honors his vision. Think About It: Why do you think people didnât believe Tesla at first? What can we learn from Teslaâs courage to dream big? 2. Charles Darwin: The Man Who Studied the Worldâs Weirdest Creatures Born: February 12, 1809 Died: April 19, 1882 When young Charles Darwin got on a ship called HMS Beagle, he didnât know he would change science forever. He sailed around the world for five years, collecting plants, animals, and fossils. On the GalĂĄpagos Islands, he noticed something curious: finches had different beaks depending on their island. Why? Darwinâs observations led him to write the theory of evolution by natural selection. It explained how animals adapt and survive. But his ideas shocked many people because they seemed to challenge religious beliefs. Despite the controversy, Darwin continued his work. His book On the Origin of Species changed how we see life on Earth. Think About It: Should scientists share their ideas even if they go against what others believe? How did traveling help Darwin make new discoveries? 3. Marie Curie: The Woman Who Glowed in the Dark Born: November 7, 1867 Died: July 4, 1934 Marie Curie was born in Poland at a time when girls were not allowed to study science. But that didnât stop her. She moved to France, worked day and night, and discovered radioactivity, a powerful energy hidden inside atoms. She and her husband, Pierre Curie, found two new elements: polonium and radium. She became the first woman to win a Nobel Prize, and the only person to win in two different sciences: physics and chemistry. Even when Pierre died in an accident, Marie continued their work. Her discoveries helped doctors treat cancerâbut working with radioactive materials also harmed her health. She died from radiation exposure, but her legacy lives on. Think About It: What challenges did Marie Curie face as a woman in science? Why is it important to balance discovery with safety? 4. Galileo Galilei: The Star Watcher Who Defied the Church Born: February 15, 1564 Died: January 8, 1642 Galileo loved looking at the stars. He built one of the first powerful telescopes and made stunning discoveries: mountains on the Moon, moons around Jupiter, and that the Earth orbits the Sunânot the other way around. This idea, called heliocentrism, went against the teachings of the Church. He was put on trial and forced to say he was wrong. But he wasnât. He spent his last years under house arrest, quietly writing. Today, Galileo is called the father of modern science for daring to question what others blindly believed. Think About It: Why do you think Galileo was punished for telling the truth? Should science always follow evidence, even if it goes against powerful beliefs? 5. Isaac Newton: The Man Who Asked âWhy?â When an Apple Fell Born: January 4, 1643 Died: March 31, 1727 One day, an apple fell from a tree, and Isaac Newton began to wonder: Why did it fall down, not sideways or up? This simple question led to his theory of gravity. Newton also invented calculus, described the laws of motion, and changed physics forever. But Newton wasnât just a geniusâhe was curious, quiet, and often worked alone. He believed everything in nature followed rules, and it was our job to discover them. Thanks to him, we understand how planets move, how rockets launch, and why you fall when you trip. Think About It: How did Newtonâs curiosity lead to great discoveries? Do you think working alone helped or hurt Newton? 6. Ada Lovelace: The First Computer Programmer Before Computers Existed Born: December 10, 1815 Died: November 27, 1852 Ada Lovelace was the daughter of the famous poet Lord Byron, but she didnât love poetryâshe loved numbers! At a time when girls were expected to sew, Ada studied mathematics. She met Charles Babbage, who designed an early computer called the Analytical Engine. Ada imagined the machine could do more than just mathâit could create music, art, and even write! She wrote what is now considered the first computer program, long before real computers were built. Think About It: How did Ada imagine something that didnât exist yet? Why do we call her a pioneer in technology? 7. Albert Einstein: The Man Who Brought Time and Space Together Born: March 14, 1879 Died: April 18, 1955 Albert Einstein wasnât always a good student. In fact, his teachers thought he was slow. But Einstein thought deeply. He asked big questions like, âWhat if you could ride a beam of light?â His theories of relativity changed how we see space, time, and gravity. He also warned the world about the dangers of nuclear weapons, even though his ideas helped create them. Einstein believed science should help people, not harm them. With his messy hair, kind smile, and brilliant mind, he remains a symbol of genius. Think About It: Can someone be bad in school but still be brilliant? Should scientists be responsible for how their inventions are used? 8. Pythagoras: The Musician Who Loved Math Born: Around 570 BC Died: Around 495 BC Long ago in ancient Greece, Pythagoras believed the universe followed numbers. He discovered the Pythagorean Theorem, a rule about triangles that helps us build houses, design computers, and navigate space. He also believed that music had math inside itâthat certain notes made perfect harmony because of mathematical ratios. Pythagoras started a secret school and taught his students to search for truth through numbers, shapes, and sound. Think About It: Why do you think Pythagoras saw math in everything? How does music relate to math? 9. Rosalind Franklin: The Woman Behind the DNA Discovery Born: July 25, 1920 Died: April 16, 1958 Rosalind Franklin loved looking closely at things. She used a special machine called X-ray crystallography to photograph molecules. One of her greatest photos, called Photo 51, showed the shape of DNA, the molecule that carries lifeâs instructions. But her work was taken without credit. Two men, Watson and Crick, used her photo to build their famous model of DNA and won the Nobel Prize. Rosalind died young and never knew how important her work became. Think About It: Why is it important to give credit in science? What can we learn from Rosalindâs quiet strength? 10. Carl Linnaeus: The Man Who Gave Names to Everything Born: May 23, 1707 Died: January 10, 1778 Have you ever wondered why a tiger is called Panthera tigris? Thatâs thanks to Carl Linnaeus, a Swedish scientist who created a way to name and organize every living thing. His system is still used today in biology. Linnaeus loved nature and spent his life collecting plants, animals, and even rocks. He believed that by organizing life, we could better understand it. Thanks to him, we now have a global âdictionary of nature.â Think About It: Why is it important to name and organize living things? How does order help us understand the world? âOn this night, we share a roof protecting us from fleets of inequity. Our unification promises a better tomorrow. Those larger than myself, sitting on their marble thrones, sipping blood from cups composed of human skin and singing songs of so-called virtue, grow weaker each moment. Their caravans are revolting. There is hope yet. There is progress! Though tonight may mark a countdown, it is still a celebration. Look at all we have done, not just for Trials but for Palatium Infra as a whole. In four years, when Iâm no longer Sovereignty, the Spoiled Purity and his people will continue to strive. So drink! Smoke! Crush up those exotic plants and snort them! We will not falter, weaken, or wane. Our influence is expanding, and somebody new opens their eyes every day. Even the Silbys of Aculeus have reached alarming potentials despite their embittered minds. So long as you relish in tonight, dance, and pray to your âdeadâ Gods, our revolution shall rise beyond the bounds of class, and when Iâm only a commoner, we shall rise again beyond our brainwashed adversaries! Cheers, my people. Cheers!â Followers raised their cups. Some clinked theirs together. Others stood still and screamed breathlessly in agreement. I smiled with courtesy, then stepped off my platform. My voice still rang across the cellar. Speeches before were grander. Those displays were supposed to be emptying, and yet this one left me bloated, swollen tight. I watched as they popped the corks of their bottles and chanted in the name of Purity. Maybe the quality of my words wasnât what mattered to them anyway, so long as I screamed loud enough. Thereâs no merit in attacking your people, a voice corrected me. âThatâs right,â I said aloud. âKnox, my-my Sovereign!â squealed a nearby devotee, jittering as he stuffed his face with catered pastries. He was one Iâd never seen before or had failed to remember. âLook what Iâve found! Itâs wine, and not the shoddy Infran kind, either. Earth-made with good fruit! I donât know how anyone managed to get their hands on this. Maybe some space travel mischief.â He giggled and held up a small glass bottle. âHow neat.â âI want you to have it, Sir.â I nodded my head. âYes, of course. Thank you.â Backing off into the midst of rowdy disciples, I clutched the bottle. What a waste of grapes. It could have been jam instead. Earthly food had a superior taste, ripe with delicate intricacies and nostalgia, but Palatium Infra had mastered the art of alcohol. Why waste your time with a drunkenness so sad and sickening? The booze of trash. Not many more followers approached me. The barren peroration must have upset them. My hands itched to submerge into my suit pockets, and my legs stood suddenly numb, wobbling. Four more years until Iâm nothing. But tonight, you are nothing. âShut up,â I told myself. Tightly packed together in the corner of the dwelling sat the Sibyls. A mound of writhing fabric and tones of skin made up their unified silhouette. I snapped the strap of the nearest gown, balancing on my hands and knees, waving the bottle before them. In their almost rodent nature, narrow noses prodded my way. Their dresses wrinkled and fell to their ankles. Knees dropped, and eyes widened. Many grumbled at me like hungry she-beasts. Those newer ones with faded curtains for hair, sunken eyes, and dirtied nails looked, hid their face, then sobbed. I imagined them in a pack together, fighting wildly against the Spoiled Purity in their rat decorumâbiting down with square teeth laced with rabies. âIâve got you all something,â I said. âGo back off to your pedestal and yap some more. We donât want it.â A woman rose from the pile and spat. âYou donât even know what it is yet. It's Earth hooch, or more likely a near-flawless replica. I figured you girls would also like a chance to enjoy yourselves tonight.â âYour playmates have been harassing us since the moment you hung the banners and opened the cellar door.â The youngest, with a striking cyan mop upon her head, uncoiled from the mass. What was she now? 20, 21? We celebrated a birthday recently, I thought as she spun around me. âI remember something about a promise. Multiple promises, actually. Are you trying to bribe us into just shutting up and taking it? Because if another sticky, 40-year-old, Earth-born virgin gropes my shoulder, Iâm going to have an aneurysm!â the girl continued. âWhy not an Infran follower? Do you like it when they touch you?â I returned her accusing tone. âIâm sorry, sweet prophets, that you feel Iâve neglected my duties. Iâll keep a better eye out. Remember, you can always just holler if somebody is bothering you. And Anwen, friend, if Iâve ever tried to bribe you with anything, it was certainly the hair dye. I mean, look at you! Such handsomeness!â I exclaimed. The other Siblys began to encircle her, uttering compliments or even announcements of their envy. Anwen disappeared in a wink with flushed cheeks back into the mound. âIâll just leave this here.â Smiling, I set down the bottle. ** â141, 143. . .â I counted each step as I trekked the staircase. There was no doubt I lost track somewhere. The ledges kept spawning under my feet, infinitely multiplying until I wasnât moving at allâswallowing me up in a whirlpool of stone. My tie still hung around my neck, and my blazer remained tied around my hips as a skirt. Streaks of red dribbled off from the cavity in my chest. It was a gorgeous marking, sensual to my fingertips as I traced its edges. Purity, oh, Purity. Purity and his wings of burnt skin. Purity and his many faces. Purity the spoiled. Purity the mutilated. The Silbys did not bother waiting for me. On bare feet, they stormed up the stairs to their room. A trail of red, though in paint unlike mine, streamed after them. None looked remotely near me as they squeaked and gossiped intangibly. I saved them, those Infran broads, enlightened them. As much as they liked to deny it, spit at me, and bask in the thought of their victimhood, in this home, they stood empowered. Youâve done well, my thoughts affirmed, though in the manner of an insincere commentator rather than a hype man. Teeth grace in tile violin goes laundry paper when. It dissolved into an intruding drivel. I rubbed my head and sniveled. âDo you need help, Knox?â called a Silby. Fattened by my coddling, her shadow fell upon me from the doorway steps ahead. I attempted counting again. There mustâve been at least another hundred between me and her. âIâm hallucinating some,â I said, breathing deeply to suppress a burp as I struggled to recall her name. Two syllables. Typically Latin, though sometimes English. Drops of slobber leaked from my mouth. âIâm hallucinating some, Tybal. Do you like your name, Tybal? I would have named you something better. Ty-Tyballinia. No, weâd have to eliminate the âballâ aspect. It sounds too crude.â âOne foot in front of the other,â she said. So I walked. Mess greeted me at the doorway. Dirtied culinary obscured the dark wooden countertops, and the sink lay running. I approached the kitchen table, sat, and set my face down upon its cool wooden surface. Assaulting my nose was the smell of neglected flowers, like soil mixed with the kind of sweet cough medicine that would have left me gagging as a child. Open windows whispered songs of the twilight hour through the vessels of busy trolleys and shooting guns. My mouth strained to vomit, but there was nothing in my stomach to regurgitate except the petals of Stultoâs bloom, which came out effortlessly in little sputters. Teetering, I stood up and brushed disgorged plant parts off the tabletop. âLove,â I said as I slogged up yet another staircase. âAre you awake?â She said sheâd wait. Somebodyâs gotten her. No, she always misses movie night. That sleepyhead, I assured myself. There was a stirring amidst the manorâs cloak of dusk. Portraits of myself, my wife, and my daughter turned to face me as the hallway lights flickered, escaping their quartz frames to penetrate my ears with nonsense. The taxidermied heads of Infran creatures bared their teeth. I stopped to stare at my favorite, an adabactor with daunting spiked tusks poking out from its forehead. Its nose remained black and sharp, and its eyes wide with malice. âWhere is my Spes, Adaba-boy? Is she sleepy?â Thereâs someone in the house. The sounds of the stirring rose along with my blood pressure. Footsteps orbited around me, drawing near and far and then near again, little dancers in the dark. The carpet immersed me in its mass of purples and blues, leaving my skin stained indigo and my vision abstracted. I toiled to reach the master bedroom across the aisle as it stretched out to me with bright lights and celestial howling, like a dove struggling in a pool of oil. Never again with Stultoâs bloom. Never again on what was already a bad night. My hand brushed the doorknob, and the high abruptly faded into only a persistent hum-buzz twirling around my brain. The portraits returned to their typical depressionâSpes posing with her ax, Ariâs school photo, and myself in the cap I wore when addressing the military with the Verbis emblem embroidered in its center. All lifeless shots. Who were they for when they captured not the subjectâs essence but only some fragment of their identity? They used to feel personal, not advertisements of some supposed characters. Servants, babysitters, and likewise civilian guests, I reminded myself, mustnât forget whose home theyâre in. Yet my body moved independently, taking Ariâs from its hook and laying it backward against the wall to hide her distant grin and tamed posture. It was time for new pictures. Sweet ones, real ones; time was ticking. I approached my own when the stirring began again. Groans and squeals erupted from the vents as if someone had set a pen of pigs loose in my crawlspace. No, not the crawlspace, my bedroom door. I turned the ruby knob. Underneath a blanket wrestled my two squealing piglets, their skins melting together beneath the layer of duvet. Fishnet leggings and manicured nails outstretched and scraped at the sheet beneath them. One raised its head, a salmon-colored man with sweat running down his forehead. Through the crack in the door, we met eyes, his Infran Dr. Sesuss nose flaring its narrow nostrils. No mark of the Spoiled Purity existed carved onto his naked body. My chest felt tight. I stepped back. I was suffocating. Spes emerged from the linens, her hair flowing down her back and her dark skin glistening in front of the bedroom window. She giggled and held the man, the blanket falling and revealing inches of her body I had not seen in months. âDarling,â whispered the rosy-faced man, âlook.â He was unfathomably ugly and grotesquely young, with beady, lifeless pupils that dilated when he faced me. The excess flesh on his face sagged while he bit down on his thin lips. My wife faced me, gasped, and strained to cover herself. Suddenly, I was a stranger. A small child who had walked into his parents having sex. I unfurled the door completely. âGet out of my house,â I said. The man stayed in place. âGet out of my house,â I repeated. âKnox,â Spes began. Tears ran down her round cheeks. âShut up!â I turned to the man, picking up a marble trophy from on top of my dresser. âGet out of my house! Iâll kill you!â âKnox!â Spes sobbed. âGod damn it! I hate you! You barely look at me. Every day, thereâs less passion. God, God, God, I donât want to fuck a dead man!â she screamed, âYou get out! Get! Get!â My hands wrapped tighter around the statue. That pig of a man was attached to her at the side, his face equipped with a scowl that challenged mine. He thought I was weak; frail like a decaying dementia-ridden senior. I imagined his skull bashed in, his scowl gone, and the feist and confidence in his face beaten into numbness. A new portrait was in order of such brutality, him as a splintered slab of wood, rashed and beaten, a carcass licking my boot. The churning in my brain had come back. Every wall shook. Clock faces came to life and rang in alarm. Indescribable noises caressed my eardrum before breaking into sorrowful weeps. Was it my own? I stared at Spes in motionless frenzy, clenched my teeth, and screamed like a siren. Passionless. What a lie! An excuse, more like. One that erased all my ventures, reducing me to a nobody. But I was not a nobody. I thought of my sect, my campaigns, my endurance through the political brutality of my empty hive-mind worldâeven my collection of literature, maps, and artifacts. I thought of daring nights alone with Spes when we were young, ravaging each other, two sardonic eggheads suddenly overcome with desire. The veins in my neck throbbed as I gasped for air. It was all I had. I threw the figurine at the manâs head. Eye shut, I heard the thud. A million singing voices of victory flooded out of the cracks in the floorboard. Proving myself a man to the woman I loved in a display of fervent violence was passion. I strained my ears for his cries, though I did not look yet. There had to be a pause, a moment of relief, where I stood tall as a skyscraper and seemingly fought to stay contained in front of my wife and her wounded, quivering paramour. Frantic footsteps rushed off the bed and past my side. I turned and grappled against myself to seize my wifeâs shoulder. âSpes!â My eyelids lifted. Escaping was the man with that same numb expression in which I had imagined him. âYouâre insane,â he said. I swiveled back towards the bed. With her curly locks flowing over her breasts and her limbs bent at her sides, Spes sat limp pressed against the headboard, her forehead bludgeoned and the statue resting on her stomach. Lips pursed and sweet, my Renaissance beauty reclined there in the guise of a squashed bug. But she was not dead. The desk ornament I flung was only the size of my shoe. Spes, that dramatist, may have been slightly hurt but was far from dead. She only wanted me to think she was to observe me at my most distraught, like a leech feeding on misery. âGet up.â Staggering toward the bed, I said. âYou wanted passion? I showed you passion. âShoved it right into your head. Of course, we both know who that gesture was meant for. . .â I fumbled to find my wit. Cold skin met my hands as I stroked her face, unable to resist checking her pulse, even though she was not dead. âI love you, Spes,â I said. Rain pelted against a nearby window. âSpes, please. Please.â No vibration answered my plea. I lifted my hand, sitting next to her now. Tears did not come. There was not any blood on the trophy, but when I picked it up, it felt to be now only a cruel instrument. It depicted a younger me in white marble, with my glasses and collared shirt being the only things painted. Both were in pink. It was a favorable color. I scrambled from the bed to vomit pure digestive bile on the rug. My stomach heaved. I ran my nails along every piece of myself I saw, a dog chasing my tail. As I slammed myself against walls and convulsed, my own heart grew ever louder in my chest. âDad? I heardââ Ariâs slippered feet hammered across the floor. âMom? Mom?â I kept my eyes on the storm. Silence fell. âShe-She isnâtâyourâ.â Gasps interrupted every syllable she spoke. âYouâre a murderer. Bad. Like they said,â she breathed, â You beat her!â The words became mush, alphabet soup. Ari ran back down the hall. âMy-My mom is dead. . . .Yes. . . Manor of the Trials Sovereignty. . .Ari Sorkin. . . Iâm afraid heâs going to hurt me,â she said, presumably over the phone. It was all too fast. I crawled onto the windowsill, opened the glass, and let myself plummet into the alley below. Gusts of wind howled. The lack of motion or sensation informed me I had passed and again lived. Another Palatium Infra, another strange planet in which the celestial endowed rotting men with the opportunity to inhabit. Was this it? Was it all just an impossible limbo of galactic traveling? My surroundings were overwhelmingly gray, an abyss of clouds. Perhaps I had now met the real coming world, and my family and old friends lived here, ready to rush to my sides, lift me up, and jump for joy. Spes would be there. She would be enraged, but at least sheâd be there. You are a bad man. You are a bad man. My eyelashes fluttered. There was a tugging sensation in my leg. The fog was wavering along with my ascendance. âNo,â I yearned, trying to grip the clouds and stick them in place. âStay with me.â But the peace was fleeting. I felt the cement under me and the moist garments clinging to my figure. My leg burned. Carefully, I craned my neck, only to observe the promenade as my surroundings. The most underwhelming of filth and danger, individually Infran. Forever my coming world. What a fool I was, having forgotten my blessing. Those idiot Gods could not tell the difference between assassination and self-infliction; a faulty insurance plan. The urge to cry at last set over me, and so I sat and wailed hot salvia into my palm, shielding my mouth to muffle the noise. Thunder echoed my hushed howling. Raindrops turned to pebbles. Under the ambiance of the stormy night, I could have sworn I heard troops stomping, guns cocking, and the chanting of my name. They had all been waiting for this. Billboards came to life, and I could only sit and spectate as the scenery flashed red. I inhaled fear and sobriety through runny nostrils. âTrials Sovereign Vsevolod âKnoxâ Sorkin is currently at large for the suspected homicide of Spes Sorkin, breaking the first term of the Sovereignty Charter. We now instruct you to report any sightings of the Earth-born, caucasian, roughly 195 centimeters tall, brown-haired, and brown-eyed man to your local Guard post. One can identify the suspected convict specifically by an occult tattoo of Purityâs Coronet on his lower back. No attempted execution or elongated punishment will take place until our Guards conduct an autopsy proving his guilt, per Lifeâs 1238 commandment. We cannot be sure when or if the Gods will revoke his blessing. Remember, when Gods frown upon strife, opt for a peaceful life. We permit all grieving festivities until Cagidus 4th. Good year!â towering buildings sang out in broadcast, repeating that same convoluted message quicker the instant it ended. Sometimes, the announcer spoke in Latin for the Infran children, other times in Chinese, Hindi, or Spanish to cater to those of irrelevant tongues. You arenât a bad man. You are a stupid boy. Puddles sloshed. Somebody was approaching. I didnât dare waste any remaining energy avoiding the Guards and their prodding blades. How did that phrase go? You dug your grave. Now lie in it. And so I embraced the cement. âKnox?â said the Guard. No, her tone was too sincere, and no authority would proceed in such a manner. There wasnât confirmation on whether or not I was armed, and it wasnât as if she could shoot me first. She was a partygoer, having just left from the cellarâs backdoor. I shooed her away with my hand. She hovered, and I discerned her shadow hesitating over my body. A man could not rot in peace. âCome on, get up! Theyâre after you!â Hands reached around my torso, struggling to handle my weight as they urged me onto my feet. That leg, the burning one, my right, trembled and bent unnaturally upon impact with the ground. The partygoer slung my arm over her shoulder, balancing me. My eyes caught a glimpse of a cyan mop. âAnwen?â I rasped, âhu-who let you out?â Keys jangled in her handsâmy keys. âI escaped,â she said casually, coercing me to walk beside her. âQuicken your pace. I just heard somebody on your front porch. âYou see that compost bin down the alley? Weâre gonna burrow right down into the depth of that. If they open it and uncover us, Iâll be on top, and I can hide you and act like Iâm just a homeless amica trying to take a nap.â With a tightening grip, she led me like livestock to the stinking crate. âI donât understand, Anwen,â I said. âTheyâre going to torture and kill you, stupid. You know theyâve been wanting to, and you just handed the opportunity to them!â âI understand that.â It was becoming increasingly challenging to hide the fragility emerging in my voice. âYou said you were escaping. Why stop and help your captor?â âWhat else could I do? Leave you there?â Attempts to shove my wounded body inside its mass of discarded fruits and vegetables began. She yanked down upon my head and submerged me in the fertilizer sea. The evidence grows indisputable, I thought as I stared at the abruptly humane Infran girl, diving in after me, that I belong here. âDamn me to hell! Iâve killed her! My love is dead!â an uncontrollable cry leaped from my mouth. âShut up! Soon youâll be, too, if you donât quiet down.â The actual noise of the Guards darted past us: disorientated marching, guns clanking against each other, cluttered belts rattling, the Latin squawking. One paused to open the binâs lid, though only rummaged through the surface layer of peat before carrying on. âWhat are they talking about? I struggle with my Latin,â I whispered. âThe search, mainly.â Aggression remained firey in Anwenâs clenched jaw. Though she sat on top of me, there was a monumental distance between our rain-soaked forms. I curled up into a ball, ducked my head between my knees, and dreamt of Spes, ignoring the stench of spoiled food rising from every crevice of my dwelling. The next coming world was due to adopt me again as I forced sleep. I prayed for a canyon of fluffy haze, where I waltzed with pale memories but found nothing but the petrifying stillness of my mind. Killed and ran. Violent as a Guard just to prove a point and watch it backfire. Why would any heaven want to welcome me? I clung to the picture of Spes in my head like it was the last ember of an extinguished flame. âDid you mean to kill her?â Anwen interrogated. âSomeone like you would immutably believe yes.â âAnd who is someone like me? You canât even treat me like a person for a moment, can you?â grating drama decorated her words. âYou know my opinions. I have not seen much of your or your breedâs faces besides that of cruelty and ignorance.â I retorted. âI just saved you! Does that make me cruel and ignorant?â âIt makes you an idiot, which is another word for somebody ignorant.â âAnd why am I an idiot?â She asked. âBecause you helping me does no good. Thank you anyhow. Now, do yourself a favor and scram.â As she bent her leg in anticipation, preparing to strike me on the forehead, I sensed an invisible withdrawal widening the gap between us. âYou never answered my question,â Anwen took me by the end of my tattered tie suddenly and started her game of shepherd and sheep over again, pulling me back up to the crateâs exit. It appeared as a shining light at the end of a maze of rubbish and mold. âNo. Of course not. Spes was my everything,â I sniffled. âI knew it. You couldnât even bring yourself to hit us, let alone murder your wife. The girls and I always figured you were sensitive.â My heart rate quickened. Today was one of humbling and miseryâone to pray a hail spike would fall from the sky as sharp as a needle, pierce into my eyelid, and lobotomize me. I wished I could have merely died or hit my head hard enough not to have to deal with it all. No, I wished I was Anwen with her snarky, careless glow and lack of depth in her eyes. As we emerged from the compost bin together, I fantasized about strangling her until her face turned purple, her weakening spirit no longer categorizing me as âsensitiveâ, but the thought could only remind me of wielding that trophy and the microscopic traces of my wifeâs tender skin tainting it, which turned my guts inside out. âThatâs why I think you could use a little help,â Anwen said, âIt seems like you canât walk, either. Your leg is all twisted up.â She undid one of her trim pigtails and handed me the band. âTake off your tie and put up your hair. âWill make you less recognizable. Then swallow your pride and stick with me.âHairHair and eyes