
Positive and negative language: Adverbs
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The chocolate cake was ___ delicious. (strong)
fairly
absolutely
Unfortunately, all the vegetables were ___ overcooked. (weak)
rather
completely
The chocolate cake was ___ delicious. (strong)
Unfortunately, all the vegetables were ___ overcooked. (weak)
The food in that new restaurant was ___ boring. (weak)
I thought the portions were ___. (weak)
That new café is ___ expensive. (strong)
I thought the tomato soup was ___ tasteless. (strong)
The staff in the hotel were ___ friendly. (weak)
When we were there the service was ___ slow. (strong)
Teaching English Introduction to the course: Language learning and teaching A 2 Characteristics of the language learners: Studying a system that aligns with international standards. A3 Cognitive factors in language learning: Addressing questions and obtaining necessary information regarding phenomena such as transfer, interference, and generalization; A4 Inductive and deductive language learning: ability and intelligence; and the phenomenon of systematic forgetting A5 Language learning methods and strategies: Familiarizing with foreign language learning methods, strategies for learning foreign languages, and communication strategies A6 International Assessment System of language skills in CEFR, IELTS, TOEFL: effective methods and strategies used to improve language skills (listening, reading, writing, speaking) A7 Psychological factors in language learning: Exploring various psychological factors such as self-esteem, shyness, risk-taking, anxiety, attitude, and motivation A8 The effectiveness of authentic materials during the learning process: The role of tasks and games in teaching foreign languages A9 Errors in language learning: Discussing types of errors, identifying and describing errors, causes of errors, and fossilized errors A10 Error correction or error analysis approaches: developing students' ability to apply their knowledge in practicing error correction A11 Age-related factors in language learning: Exploring types of comparisonand contrast, focusing on topics such as the age hypothesis and bilingualism, and providing a detailed explanation of these concepts A12 Teaching grammar: Studying grammar teaching methods; deductive and inductive approaches in grammar teaching; A13 Teaching grammar through context: linguistic intuition; language phenomena; using grammatical dictionaries; analyzing grammatical tasks; and designing exercises, tasks, and tests through completing grammarbased activities. 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In international assessment systems such as CEFR, IELTS, and TOEFL, grammar accuracy and lexical resource A 17 Teaching pronunciation: Understanding the importance of pronunciation for successful communication; teaching stress; teaching intonation A18 Modern technologies in teaching pronunciation A19 Error correction methods: watching to various experiences in this area and analyzing video lessons from international experts in the field A20 Analysis of skill integration in language learning: Understanding the stages of developing skill integration; integration of the four language skills; task-based integration; and project-based integration. A21 Teaching listening comprehension A22 Modern technologies in teaching listening comprehension A23 Teaching Speaking A24 Modern technologies in teaching Speaking A25 Teaching Reading A26 Modern technologies in teaching Reading A27 Teaching Writing A28 Modern technologies in teaching Writing A29 The role and importance of translation in teaching a foreign language A30 Module 2. International standards for teaching and assessment Classroom Language: The teacher's actions; the teacher's voice; the teacher's intonation; using the foreign language in the classroom A31 Foreign language environment: asking questions in the foreign language, giving instructions in the foreign language, providing oral explanations in the foreign language, and issues related to the use of the native language in the foreign language class. A 32 Designing curriculum: Studying, analyzing, and working with curricula designed for schools, lyceums, and colleges. 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A41 Differences between methods of teaching foreign languages: practical application of modern methods in language teaching; foreign experiences in language teaching: the grammar-translation method; the method of conducting lessons entirely in the foreign language; the audio-linguistic method; and communicative methods. A42 Methods used in the local environment and their analysis: Discussion of the positive and negative aspects of various methods; language and culture; teaching/learning processes; the role of the native language in learning a foreign language; and the psychological foundations of foreign language teaching. A43 Teaching a foreign language through computer technologies A44 Types of independent work and its implementation A45 Principles of Assessment in foreign language teaching А46 Issues in Language Assessment А47 Alternatives in Assessment А48 Test methods. Methods and criteria for assessing language aspects: written expression, reading, listening comprehension, speaking, А49 integrating language skills: vocabulary; grammar; alternative forms of assessment; planning assessment; critical analysis; principles for designingtest tasks: scientific rigor, consistency, conciseness, clarity, informality, logical sequence, and systematic approach. А50 Foreign language for ESP. Studying and analyzing needs; setting objectives for teaching a foreign language in a specific field or professional area; defining teaching approaches in curriculum development; and discussing topics related to these areas. А51 Selecting textbooks, materials and resources А52 Content-based Instruction (CBI) А53 Strategies-based Instruction А54 Lifelong Learning: Teacher development, PreSETT, InSETT А55 The Role of Teaching Practice A56 Organization and implementation of compulsory and non-compulsory course process in foreign language teaching A57 Organization in and outclass activities A58 Defining the goals and content of foreign language teaching at various levels of the education system in the Republic of Uzbekistan: evaluating educational materials; adapting educational materials; creating educational materials; and discussing the role of the foreign language teacher in specialized fields to gain relevant information. A59 The role of independent study skills: foreign language focused on reading, research and study skills; make revision questions. incclude mcq question. answer the question. true false
Electrostatics The section of CBSE Class 12 Physics electrostatic potential and capacitance notes mainly deals with the in-depth analysis of electromagnetic phenomena when they are not performing any movements. Additionally, it is divided into ten further sub-topics to study the companion processes of reaching the state. These are - 1. Electric charge In this section of Physics ch 2 Class 12 notes, you get to learn about the basic features of electric charge and its expression in Physics. Along with its basics, the sections help to understand the full potential of charge. Different aspects of Charge included in Class 12 Physics Chapter 2 notes are - Definition Type: Positive and Negative Charge Unit and dimensional formula Point Charge Properties of Charge Comparison of Charge and Mass Methods of Charging Electroscope 2. Coulomb's Law Force is created when charges of opposite signs attract each other, and they repulse if the signs are the same. Coulomb's law tries to define this phenomenon through a mathematical formula, explicitly mentioned in Physics Class 12 notes Chapter 2. Moreover, there is key information about the variation of the constant k and its effect on a medium. Coulomb's law's vector form and the principle of superimposition are also explained in ch 2 Physics Class 12 notes. (Image will be uploaded soon) 3. Electric Field As stated in Class 12 Physics Chapter 2 notes, every positively or negatively charged particle has their respective electric fields. It feels a force at the time of interaction which might be attraction or repulsion. As it arises from electric charge, it is crucial to know about its different parts like - Electric field intensity Relation between electric force and electric field Super imposition of electric field Point charge Continuous charge distributions Properties of Electric Field Lines Motion of Charged Particles in an Electric field Learning more about the electric field from electric potential and capacitance notes Class 12 helps a student to get a grasp of upcoming chapters. 4. Electric Potential Energy When energy helps a charge to move from an electric field, it is known as the Electric Potential Energy. This section of electrostatic chapter Class 12 notes requires a student to study the Electron volt (eV), and the potential energy that an n number of charges can hold. 5. Electric Potential This section of Class 12 Physics Chapter 2 notes focuses on in-depth learning of Electric Potential or Voltage. Basically, it defines the potential movement of energy. 6. Relation between Electric Field and Potential Apart from knowing more about the relationship between the two values, Physics Class 12 Chapter 2 notes also discuss equipotential surfaces. 7. Electric Dipole Essentially, 'Dipoles' are two opposite points of charge represented with q and –q, with their distance between each other being 2a. Electric Dipoles are crucial in your study of Physics Class 12 Chapter 2 notes to learn more about electric fields and their potential. Additionally, Class 12 Physics Chapter 2 notes focus on the influence of electric dipoles on a uniform electric field mainly through Force and Torque, Work, and Potential Energy. In the last part of Electrostatics, further focus is on using the formulas to their fullest potential. It includes subsections of Electric Field, Electric Potential Energy, Electric Potential, and Electric Dipole. In the notes for electrostatic potential and capacitance, you will find proper solutions accompanied by clear and crisp diagrams for better understanding. 8. Gauss's Law Apart from just discussing the Gauss's Law, in Physics Class 12 ch 2 notes there is a thorough explanation of its properties and applications. The Gauss' Law states that net electric flux passing through a hypothetical closed surface is equal to the net electric charge present within the same closed surface. Being a broad part of the whole chapter, you may need to spend a little more time on it. Moving forward, it starts discussing the properties of conductors in relation to Gauss's Law. The Class 12 Physics notes Chapter 2 perfectly defines the journey to Gauss' Law from Coulomb's Law. Here is the Gauss's Law present in the Class 12 Physics ch 2 notes, (image will be uploaded soon) 9. Capacitors There is a dedicated section about Capacitors in the Class 12 Physics Chapter 2 notes elucidating its functions and importance as storage of potential electric energy. After explaining the structure of a capacitor, it points out the different types, parallel plate, spherical and cylindrical. The section of Chapter 2 notes of Physics Class 12 is further divided into subheads like: Properties of an ideal battery Grouping of capacitors Simple circuits (Series and Parallel) Dielectric Van de Graaff generator Combination of drops Charge distribution method Wheatstone Bridge-based circuit Extended Wheatstone Bridge Infinite network of capacitors Redistribution of charge between two capacitors Vedantu prepares the Class 12 Physics Chapter 2 notes with help from subject matter experts. In the PDF, you get a comprehensive idea of the topic along with potential answers to the most asked questions. Furthermore, the detailed explanation on each section and subsections are written in a simple language allows a student to ace their exams with wholesome knowledge. These Physics Chapter 2 Class 12 notes are going to be one of the best supplementary study materials besides a student’s textbooks. Visit the Vedantu website or download the app to get your hands on all important notes! Important Questions A charge of 4 × 10–8C is uniformly distributed on the surface of a spherical conductor, having a radius of 15 cm. Determine the electric field just outside this sphere at a point that is 15 cm from the centre of this sphere. Determine the capacitance given that the distance between the two plates has been reduced by half and the parallel plate capacitor holds a capacitance of 20 pF (where 1pF = 10-12 F) having air between the two plates. What will be the total capacitance of a combination where three capacitors, each having a capacitance of 20 pF, are connected in series. A square having a side of 10 cm has a 500 µC charge at its centre. Determine the work done to move a charge of 10 µC between two points that are diagonally opposite each other on the square. At an equatorial point, what will be the electrostatic potential because of an electric dipole? Calculate the work done to move a test charge, q, through a length of 1 cm along the equatorial axis of an electric dipole? Polarisation A capacitor has its plates enclosed in a medium that can be filled by insulating substances. A net dipole moment is then induced by an electric field in the dielectric. This event causes the field in an opposite direction. Equipotential Surface An equipotential surface is a type of surface where the potential always has a constant value. If considered as a point charge, the concentric spheres that are centred at a particular area of this charge are basically equipotential surfaces. Advantages of Vedantu's Revision Notes: A Comprehensive Resource for Effective Learning There are several reasons why one may refer to Vedantu's revision notes for studying a subject like Electrostatic Potential and Capacitance. Here are some key points: Comprehensive Coverage: Vedantu's revision notes provide a comprehensive coverage of the entire topic, ensuring that all important concepts and subtopics are included. Concise and Organized: The notes are designed to be concise, focusing on the key points and core ideas. They are organized in a structured manner, making it easy for students to navigate and revise the content. Simplified Explanation: The revision notes offer simplified explanations of complex concepts, making them more accessible and easier to understand. This helps students grasp the material more effectively. 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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 Desirée Nieuwenhuis | Natàlia 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. 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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 ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. 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Contact with the Americas In 1001, Viking sailors led by Leif Erikson reached the eastern tip of North America. Archaeologists have found evidence of the Viking settlement of Vinland in present-day Newfoundland, Canada. The Vikings did not stay in Vinland long and no one is sure why they left. However, Viking stories describe fierce battles with Skraelings, the Viking name for the Inuit. Evidence suggests that Asians continued to cross the Bering Sea into North America after the last ice age ended. Some scholars believe that ancient seafarers from Polynesia may have traveled to the Americas using their knowledge of the stars and winds. Modern Polynesians have sailed canoes thousands of miles in this way. Still others think that fishing boats from China and Japan blew off course and landed on the western coast of North or South America. Perhaps such voyages occurred. If so, they were long forgotten. Before 1492, the peoples of Asia and Europe had no knowledge of the Americas and their remarkable civilizations. The Voyages of Columbus Portuguese sailors had pioneered new routes around Africa toward Asia in the late 1400s. Spain, too, wanted a share of the riches. King Ferdinand and Queen Isabella hoped to keep their rival, Portugal, from controlling trade with India, China, and Japan. They agreed to finance a voyage of exploration by Christopher Columbus. Columbus, an Italian sea captain, planned to reach the East Indies by sailing west across the Atlantic. Finding a sea route straight to Asia would give the Spanish direct access to the silks, spices, and precious metals of Asia. The spice trade was a major cause for European exploration and a reason the Spanish rulers supported Columbus’s voyage. They also wanted wealth from any source. “Get gold,” King Ferdinand said to Columbus. “Humanely if possible, but at all hazards—get gold.” Crossing the Atlantic In August 1492, Columbus set out with three ships and about 90 sailors. As captain, he commanded the largest vessel, the Santa María. The other ships were the Niña and the Pinta. After a brief stop at the Canary Islands, the little fleet continued west into unknown seas. Fair winds sped them along, but a month passed without the sight of land. Some sailors began to grumble. They had never been away from land for so long and feared being lost at sea. Still, Columbus sailed on. On October 7, sailors saw flocks of birds flying southwest. Columbus changed course to follow the birds. A few days later, crew members spotted tree branches and flowers floating in the water. At 2 a.m. on October 12, the lookout on the Pinta spotted white cliffs shining in the moonlight. “Tierra! Tierra!” he shouted. “Land! Land!” At dawn, Columbus rowed ashore and planted the banner of Spain. He was convinced that he had reached the East Indies in Asia. He called the people he found there “Indians.” In fact, he had reached islands off the coasts of North America and South America in the Caribbean Sea. These islands later became known as the West Indies. For three months, Columbus explored the West Indies. To his delight, he found signs of gold on the islands. Eager to report his success, he returned to Spain. Columbus Claims Lands for Spain In Spain, Columbus presented Queen Isabella and King Ferdinand with gifts of pink pearls and brilliantly colored parrots. Columbus brought with him many things that Europeans had never seen before: tobacco, pineapples, and hammocks used for sleeping. Columbus also described the “Indians” he had met, the Taino (ty noh). The Taino, he promised, could easily be converted to Christianity and could also be used as slaves. The Spanish monarchs were impressed. They gave Columbus the title Admiral of the Ocean Sea. They also agreed to finance future voyages. The promise of great wealth, and the chance to spread Christianity, gave them a reason to explore further. Columbus made three more voyages across the Atlantic. In 1493, he founded the first Spanish colony in the Americas, Santo Domingo, on an island he called Hispaniola (present-day Haiti and the Dominican Republic). A colony is an area settled and ruled by the government of a distant land. Columbus also explored present-day Cuba and Jamaica. He sailed along the coasts of Central America and northern South America. He claimed all of these lands for Queen Isabella of Spain. Columbus proved to be a better explorer than governor. During his third expedition, settlers on Hispaniola complained of his harsh rule. Queen Isabella appointed an investigator, who sent Columbus back to Spain in chains. In the end, the queen pardoned Columbus, but he never regained the honors he had won earlier. He died in 1506, still convinced that he had reached Asia. The Impact of Columbus’s Voyages Columbus has long been honored as the bold sea captain who “discovered America.” Today, we recognize that American Indians had discovered and settled these lands long before 1492. We also recognize that Columbus and the Europeans who followed him treated the ancient inhabitants of the Americas brutally. Still, Columbus’s voyages did change history. They marked the beginning of lasting contact among the peoples of Europe, Africa, and the Americas. For a great many American Indians, contact had tragic results. Columbus and those who followed were convinced that European culture was superior to that of the Indians. The Spanish claimed Taino lands and forced the Taino to work in gold mines, on ranches, or in Spanish households. Many Taino died from harsh conditions or European diseases. The Taino population was wiped out. Still, the voyages of Columbus signaled a turning point for the Americas. A turning point is a moment in history that marks a decisive change. Curious Europeans saw the new lands as a place where they could settle, trade, and grow rich. Spanish Exploration Continues After the voyages of Columbus, the Spanish explored and settled other Caribbean islands that Columbus had found. They sought gold, land for crops, people to enslave, and converts to Christianity for the Spanish crown. By 1511, they had conquered Puerto Rico, Jamaica, and Cuba. They also explored the eastern coasts of North America and South America in search of a western route to Asia. In 1513, Vasco Núñez de Balboa (bal boh uh) crossed the Isthmus of Panama. American Indians had told him that a large body of water lay to the west. With a party of Spanish soldiers and Indians, Balboa reached the Pacific Ocean and claimed the ocean for Spain. The Spanish had no idea how wide the Pacific was until a sea captain named Ferdinand Magellan (muh jel un) sailed across it. The expedition—made up of five ships and about 250 crew members—left Spain in 1519. Fifteen months later, it cut through the stormy southern tip of South America by way of what is now known as the Strait of Magellan and entered the Pacific Ocean. Crossing the vast Pacific, the sailors ran out of food: Primary Source “We remained 3 months and 20 days without taking in provisions or other refreshments and ate only old biscuit reduced to powder, full of grubs and stinking from the dirt which rats had made on it. We drank water that was yellow and stinking.” —Antonio Pigafetta, The Diary of Antonio Pigafetta Magellan himself was killed in a battle with the local people of the Philippine Islands off the coast of Asia. In 1522, only one ship and 18 sailors returned to Spain. They were the first people to circumnavigate, or sail completely around, the world. In doing so, they had found an all-water western route to Asia. Europeans became aware of the true size of the Earth. How Did the Columbian Exchange Affect the Rest of the World? The encounter between the peoples of the Eastern and Western Hemispheres sparked a global exchange of goods and ideas. Because it started with the voyages of Columbus, this transfer is known as the Columbian Exchange. The Columbian Exchange refers to a biological and cultural exchange of animals, plants, human populations, diseases, food, government, technology, the arts, and languages. The exchange went in both directions. Europeans learned much from American Indians. At the same time, Europeans contributed in many ways to the culture of the Americas. This exchange also brought about many modifications, or changes, to the physical environment of the Americas, with both positive and negative results. Changing Environments Europeans introduced domestic animals such as chickens from Europe and Africa. European pigs, cattle, and horses often escaped into the wild and multiplied rapidly. Forests and grasslands were converted to pastures. As horses spread through what would become the United States, Indians learned to ride them and used them to carry heavy loads. Plants from Europe and Africa changed the way American Indians lived. The first bananas came from the Canary Islands. By 1520, one Spaniard reported that banana trees had spread “so greatly that it is marvelous to see the great abundance of them.” Oranges, lemons, and figs were also new to the Americas. In North America, explorers also brought such plants as bluegrass, the daisy, and the dandelion. These plants spread quickly in American soil and modified American grasslands. Tragically, Europeans also brought new diseases, such as smallpox and influenza. American Indians had no resistance to these diseases. Historians estimate that within 75 years, diseases from Europe had killed almost 90 percent of the people in the Caribbean Islands and in Mexico. American Indian Influences on Europe, Africa and Asia American Indians introduced Europeans to valuable food crops such as corn, potatoes, sweet potatoes, beans, tomatoes, manioc, squash, peanuts, pineapples, and blueberries. Today, almost half the world’s food crops come from plants that were first grown in the Americas. Europeans carried the new foods with them as they sailed around the world. Everywhere, people’s diets changed and populations increased. In South Asia, people used American hot peppers and chilies to spice stews. Chinese peasants began growing corn and sweet potatoes. Italians made sauces from tomatoes. People in West Africa grew manioc and corn. European settlers often adopted American Indian skills. In the North, Indians showed Europeans how to use snowshoes and trap beavers and other fur-bearing animals. European explorers learned how to paddle Indian canoes. Some leaders studied American Indian political structures. In the 1700s, Benjamin Franklin admired the Iroquois League and urged American colonists to unite in a similar way. Positive and Negative Consequences Through the Columbian Exchange, Europeans and American Indians modified their environments and gained new resources and skills. At the same time, warfare and disease killed many on both sides. Europeans viewed expansion positively. They gained great wealth, explored trade routes, and spread Christianity. Yet their farming, mining, and diseases took a toll on the physical environment and left many American Indians dead. Despite these negatives, the Columbian Exchange shaped the modern world, including what would become the United States.
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