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To be,am is are,times in english,possessive pronouns,articles a,an,the,days of week,months,seasons,plural ,modal verbs can,may,must,
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“On 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 I’m 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 “dead” Gods, our revolution shall rise beyond the bounds of class, and when I’m only a commoner, we shall rise again beyond our brainwashed adversaries! Cheers, my people. Cheers!” 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 wasn’t what mattered to them anyway, so long as I screamed loud enough. There’s no merit in attacking your people, a voice corrected me. “That’s right,” I said aloud. “Knox, my-my Sovereign!” squealed a nearby devotee, jittering as he stuffed his face with catered pastries. He was one I’d never seen before or had failed to remember. “Look what I’ve found! It’s wine, and not the shoddy Infran kind, either. Earth-made with good fruit! I don’t know how anyone managed to get their hands on this. Maybe some space travel mischief.” He giggled and held up a small glass bottle. “How neat.” “I want you to have it, Sir.” I nodded my head. “Yes, of course. Thank you.” 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 I’m nothing. But tonight, you are nothing. “Shut up,” 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 decorum–biting down with square teeth laced with rabies. “I’ve got you all something,” I said. “Go back off to your pedestal and yap some more. We don’t want it.” A woman rose from the pile and spat. “You don’t 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.” “Your playmates have been harassing us since the moment you hung the banners and opened the cellar door.” 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. “I 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, I’m going to have an aneurysm!” the girl continued. “Why not an Infran follower? Do you like it when they touch you?” I returned her accusing tone. “I’m sorry, sweet prophets, that you feel I’ve neglected my duties. I’ll keep a better eye out. Remember, you can always just holler if somebody is bothering you. And Anwen, friend, if I’ve ever tried to bribe you with anything, it was certainly the hair dye. I mean, look at you! Such handsomeness!” 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. “I’ll just leave this here.” Smiling, I set down the bottle. ** “141, 143. . .” 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 wasn’t moving at all–swallowing 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. You’ve 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. “Do you need help, Knox?” called a Silby. Fattened by my coddling, her shadow fell upon me from the doorway steps ahead. I attempted counting again. There must’ve been at least another hundred between me and her. “I’m hallucinating some,” 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. “I’m hallucinating some, Tybal. Do you like your name, Tybal? I would have named you something better. Ty-Tyballinia. No, we’d have to eliminate the ‘ball’ aspect. It sounds too crude.” “One foot in front of the other,” 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 Stulto’s bloom, which came out effortlessly in little sputters. Teetering, I stood up and brushed disgorged plant parts off the tabletop. “Love,” I said as I slogged up yet another staircase. “Are you awake?” She said she’d wait. Somebody’s gotten her. No, she always misses movie night. That sleepyhead, I assured myself. There was a stirring amidst the manor’s 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. “Where is my Spes, Adaba-boy? Is she sleepy?” There’s 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 Stulto’s 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 depression–Spes posing with her ax, Ari’s 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 subject’s 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, mustn’t forget whose home they’re in. Yet my body moved independently, taking Ari’s 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. “Darling,” whispered the rosy-faced man, “look.” 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. “Get out of my house,” I said. The man stayed in place. “Get out of my house,” I repeated. “Knox,” Spes began. Tears ran down her round cheeks. “Shut up!” I turned to the man, picking up a marble trophy from on top of my dresser. “Get out of my house! I’ll kill you!” “Knox!” Spes sobbed. “God damn it! I hate you! You barely look at me. Every day, there’s less passion. God, God, God, I don’t want to fuck a dead man!” she screamed, “You get out! Get! Get!” 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 world–even 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 man’s 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 wife’s shoulder. “Spes!” My eyelids lifted. Escaping was the man with that same numb expression in which I had imagined him. “You’re insane,” 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. “Get up.” Staggering toward the bed, I said. “You wanted passion? I showed you passion. ‘Shoved it right into your head. Of course, we both know who that gesture was meant for. . .” 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. “I love you, Spes,” I said. Rain pelted against a nearby window. “Spes, please. Please.” 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. “Dad? I heard–” Ari’s slippered feet hammered across the floor. “Mom? Mom?” I kept my eyes on the storm. Silence fell. “She-She isn’t—your—.” Gasps interrupted every syllable she spoke. “You’re a murderer. Bad. Like they said,” she breathed, “ You beat her!” The words became mush, alphabet soup. Ari ran back down the hall. “My-My mom is dead. . . .Yes. . . Manor of the Trials Sovereignty. . .Ari Sorkin. . . I’m afraid he’s going to hurt me,” 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 she’d 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. “No,” I yearned, trying to grip the clouds and stick them in place. “Stay with me.” 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. “Trials Sovereign Vsevolod “Knox” 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 Purity’s Coronet on his lower back. No attempted execution or elongated punishment will take place until our Guards conduct an autopsy proving his guilt, per Life’s 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!” 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 aren’t a bad man. You are a stupid boy. Puddles sloshed. Somebody was approaching. I didn’t 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. “Knox?” said the Guard. No, her tone was too sincere, and no authority would proceed in such a manner. There wasn’t confirmation on whether or not I was armed, and it wasn’t as if she could shoot me first. She was a partygoer, having just left from the cellar’s 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. “Come on, get up! They’re after you!” 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. “Anwen?” I rasped, “hu-who let you out?” Keys jangled in her hands–my keys. “I escaped,” she said casually, coercing me to walk beside her. “Quicken your pace. I just heard somebody on your front porch. ‘You see that compost bin down the alley? We’re gonna burrow right down into the depth of that. If they open it and uncover us, I’ll be on top, and I can hide you and act like I’m just a homeless amica trying to take a nap.” With a tightening grip, she led me like livestock to the stinking crate. “I don’t understand, Anwen,” I said. “They’re going to torture and kill you, stupid. You know they’ve been wanting to, and you just handed the opportunity to them!” “I understand that.” It was becoming increasingly challenging to hide the fragility emerging in my voice. “You said you were escaping. Why stop and help your captor?” “What else could I do? Leave you there?” 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. “Damn me to hell! I’ve killed her! My love is dead!” an uncontrollable cry leaped from my mouth. “Shut up! Soon you’ll be, too, if you don’t quiet down.” 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 bin’s lid, though only rummaged through the surface layer of peat before carrying on. “What are they talking about? I struggle with my Latin,” I whispered. “The search, mainly.” Aggression remained firey in Anwen’s 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. “Did you mean to kill her?” Anwen interrogated. “Someone like you would immutably believe yes.” “And who is someone like me? You can’t even treat me like a person for a moment, can you?” grating drama decorated her words. “You know my opinions. I have not seen much of your or your breed’s faces besides that of cruelty and ignorance.” I retorted. “I just saved you! Does that make me cruel and ignorant?” “It makes you an idiot, which is another word for somebody ignorant.” “And why am I an idiot?” She asked. “Because you helping me does no good. Thank you anyhow. Now, do yourself a favor and scram.” As she bent her leg in anticipation, preparing to strike me on the forehead, I sensed an invisible withdrawal widening the gap between us. “You never answered my question,” 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 crate’s exit. It appeared as a shining light at the end of a maze of rubbish and mold. “No. Of course not. Spes was my everything,” I sniffled. “I knew it. You couldn’t even bring yourself to hit us, let alone murder your wife. The girls and I always figured you were sensitive.” My heart rate quickened. Today was one of humbling and misery–one 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 “sensitive”, but the thought could only remind me of wielding that trophy and the microscopic traces of my wife’s tender skin tainting it, which turned my guts inside out. “That’s why I think you could use a little help,” Anwen said, “It seems like you can’t walk, either. Your leg is all twisted up.” She undid one of her trim pigtails and handed me the band. “Take off your tie and put up your hair. ‘Will make you less recognizable. Then swallow your pride and stick with me.”
All living things are made up of one or more cells. A cell is the smallest unit that can carry on all of the processes of life. Beginning in the 17th century, curious naturalists were able to use microscopes to study objects too small to be seen with the unaided eye. Their studies led them to propose the cellular basis of life. Hooke In 1665, English scientist Robert Hooke studied nature by using an early light microscope, such as the one in Figure 4-1a. A light micro- scope is an instrument that uses optical lenses to magnify objects by bending light rays. Hooke looked at a thin slice of cork from the bark of a cork oak tree. “I could exceedingly plainly perceive it to be all perforated and porous,” Hooke wrote. He described “a great many little boxes” that reminded him of the cubicles or “cells” where monks live. When Hooke focused his microscope on the cells of tree stems, roots, and ferns, he found that each had similar little boxes. The drawings that Hooke made of the cells he saw are shown in Figure 4-1b. The “little boxes” that Hooke observed were the remains of dead plant cells, such as the cork cells shown in Figure 4-1c. SECTION 1 OBJECTIVES ● Name the scientists who first observed living and nonliving cells. ● Summarize the research that led to the development of the cell theory. ● State the three principles of the cell theory. ● Explain why the cell is considered to be the basic unit of life. VOCABULARY cell cell theory Robert Hooke used an early microscope (a) to see cells in thin slices of cork. His drawings of what he saw (b) indicate that he had clearly observed the remains of cork cells (300) (c). FIGURE 4-1 (a) (b) (c) Copyright © by Holt, Rinehart and Winston. All rights reserved. 70 CHAPTER 4 Leeuwenhoek The first person to observe living cells was a Dutch trader named Anton van Leeuwenhoek. Leeuwenhoek made microscopes that were simple and tiny, but he ground lenses so precisely that the magnification was 10 times that of Hooke’s instruments. In 1673, Leeuwenhoek, shown in Figure 4-2a, was able to observe a previ- ously unseen world of microorganisms. He observed cells with green stripes from an alga of the genus Spirogyra, as shown in Figure 4-2b, and bell-shaped cells on stalks of a protist of the genus Vorticella, as shown in Figure 4-2c. Leeuwenhoek called these organisms animalcules. We now call them protists. THE CELL THEORY Although Hooke and Leeuwenhoek were the first to report observ- ing cells, the importance of this observation was not realized until about 150 years later. At this time, biologists began to organize information about cells into a unified understanding. In 1838, the German botanist Matthias Schleiden concluded that all plants were composed of cells. The next year, the German zoologist Theodor Schwann concluded the same thing for animals. And finally, in his study of human diseases, the German physician Rudolf Virchow (1821–1902) noted that all cells come from other cells. These three observations were combined to form a basic theory about the cel- lular nature of life. The cell theory has three essential parts, which are summarized in Table 4-1. Anton van Leeuwenhoek (1632–1723) is shown here with one of his hand-held lenses (a). Leeuwenhoek observed an alga of the genus Spirogyra (b) and a protist of the genus Vorticella (c). FIGURE 4-2 TABLE 4-1 The Cell Theory All living organisms are composed of one or more cells. Cells are the basic units of structure and function in an organism. Cells come only from the reproduction of existing cells. (a) (b) (c) www.scilinks.org Topic: Cell Theory Keyword: HM60241 mb06se_csfs01.qxd 5/18/07 10:54 AM Page 70
Gr''ade 3 Questions based on this chapter: English Alexander was a king of the ancient Greek kingdom of Macedonia. By the age of thirty, he had created one of the largest empires in the world, stretching from Greece to northwestern India. When Alexander was young, a trader brought a horse which was difficult to mount. Let us read about how Alexander tames the horse. One day King Philip bought a fine horse. He was a strong animal and the king paid a high price for him. But he was wild and no man could mount him, or do anything at all with him. This horse is really wild. It cannot be tamed by the royal men. Many have tried and failed. We tried everything possible, your Majesty. We tried to whip him but that only made him worse. Glossary wild rough/harsh mount a horse to climb onto the back of a horse to tame to control whip to beat using a long rope King Philip asked his men to take the horse away. It is a pity to send such a fine horse away. I think the men do not know how to tame him. I can try taming this beautiful horse. Perhaps you can do better than them. But be careful, my son. You are still very young to mount this violent animal. Alexander wanted to (mount/feed/tame/ ride) the horse. If you would give me the order, I will try. I am sure I can manage this horse better than anyone else. Antonym(s) worse x better young x old fail x succeed If I fail, I will pay you the price of the horse, Father. The courtiers told Alexander that it might be dangerous for a young boy to try taming the wild horse. They laughed at him. Alexander went near the horse and turned his head towards the sun. He had noticed that the horse was afraid of his own shadow. I will name you Bucephalus. Stay calm and I will do no harm. The horse was afraid of his own (body/courtiers/King Philip/shadow). English He then spoke gently to the horse. Bucephalus means 'ox-head'— head of an ox, in Ancient Greek. When he had quietened him a little, he made a quick spring and leapt upon the horse's back. I thought the little prince would be killed by this dangerous animal. What a miracle! The horse has recognized the young prince as his master. Alexander let the horse run. When Bucephalus had become tired of running, Alexander reined him in and rode back to the place where his father was standing. Glossary noticed (here) to see afraid scared/frightened calm quiet gently softly quietened to become calmer and less noisy a miracle a wonder/unusual event to rein to check or guide a horse Look at the young prince! He is mounted well! But the horse is still wild! Antonym(s); laughed x cried afraid x brave. English When he reached the place where his father was standing, he leapt to the ground. His father ran and kissed him. Dear Father! I shall add My son! Macedonia is a small kingdom more territories and bring for you. You must seek a larger kingdom glory to our kingdom. that will be worthy of you. Fascinating Fact(s) Alexandria Bucephalus was a city founded by Alexander in memory of his loyal horse Bucephalus. During Alexander's invasion of India, he had fought against the Indian King, Porus, near the river Hydaspes (modern day river Jhelum, Pakistan). His horse Bucephalus died there and he honoured his horse by naming the city after it. Antonym(s) worthy x unworthy proud x ashamed You have carried me across countries and stood bravely beside me as I fought to win the numerous fierce battles. You have saved my life many times. I am truly proud of you, Bucephalus. (Mesopotamia/Minneapolis/ Macedonia/Minnesota) was a small kingdom for Alexander to rule. Glossary numerous many fierce strong and violent Alexander and Bucephalus were said to be always together, for when one of them was seen, the other was sure to be not far away. Bucephalus would never allow anyone to mount him, but his master. Alexander became the most famous king and warrior, and for that reason, he is called 'Alexander the Great!.
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. 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)— 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 ‘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. 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, Widén 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) 1999–2004. 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, Müller 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 “obesity paradox” 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 gover
Alright, Isti — here’s a longer and more detailed English version of the Isaac Newton text, still written at a level that’s accessible for Grade 4 students, but rich enough in information to meet PISA literacy expectations and EF A2-level vocabulary. I’ve kept sentences short, clear, and with explanations for new concepts so it’s easier for young learners to follow, while still including both famous facts and lesser-known stories. ⸻ 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 — a clock that tells the time by using the shadow of the sun. 💡 Did you know? The sundial marks that Isaac carved as a boy can still be seen today on the wall of his old house. ⸻ 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. ⸻ The Falling Apple and Gravity One of the most famous stories about Newton is the falling apple. One afternoon, Isaac sat in his mother’s garden and saw an apple drop from a tree. This made him think: “Why does the apple fall straight down? Why doesn’t it fly up into the sky?” From this question, Newton began to think about gravity — an invisible force that pulls objects toward each other. Gravity is what keeps our feet on the ground. It’s also what keeps the Moon moving around the Earth and the planets moving around the Sun. 💡 Fun fact: The apple did not hit Newton’s head. That’s just a story people made up later to make the tale more exciting. ⸻ Newton’s Three Laws of Motion Newton studied movement and wrote three important rules: 1. Objects stay still or keep moving unless something makes them change. • Example: A ball will not roll unless you push it. 2. The bigger the push, the bigger the movement. • Example: If you kick a ball harder, it will go faster and farther. 3. Every action has an equal and opposite reaction. • 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. ⸻ Discoveries in Light and Color Newton also studied light. He found that white light is not just one color — it is made of many colors. He used a glass prism to split sunlight into a rainbow. This helped scientists understand how colors work. ⸻ 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. ⸻ 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. 💡 Did you know? Newton also studied alchemy — an old kind of science where people tried to turn metal into gold. He never succeeded, but it showed how wide his interests were. ⸻ 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. ⸻ 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 Newton’s laws and ideas. 💬 Newton once said: “If I have seen further, it is by standing on the shoulders of giants.” 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, “Can we catch the light?” 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 air—like 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 didn’t believe Tesla at first? What can we learn from Tesla’s courage to dream big? 2. Charles Darwin: The Man Who Studied the World’s Weirdest Creatures Born: February 12, 1809 Died: April 19, 1882 When young Charles Darwin got on a ship called HMS Beagle, he didn’t know he would change science forever. He sailed around the world for five years, collecting plants, animals, and fossils. On the Galápagos Islands, he noticed something curious: finches had different beaks depending on their island. Why? Darwin’s 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 didn’t 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 cancer—but 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 Sun—not 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 wasn’t. 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 “Why?” 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 wasn’t just a genius—he 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 Newton’s 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 didn’t love poetry—she 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 math—it 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 didn’t 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 wasn’t always a good student. In fact, his teachers thought he was slow. But Einstein thought deeply. He asked big questions like, “What if you could ride a beam of light?” 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 it—that 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 life’s 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 Rosalind’s 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? That’s 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 “dictionary of nature.” Think About It: Why is it important to name and organize living things? How does order help us understand the world?
Broken windows are covered. Floorboards are patched and doors screwed back on. The road that was ruined by German tanks is shovelled and raked smooth. Boot-shaped bruises turn yellow then fade and disappear. Flowers grow and spread across the ugly German footprints stomped into garden beds. The village looks pretty once more. School stops for the summer and everyone is put to work on the kolkhoz, the village farm. Women and big boys begin harvesting the barley crops in the outer fields. The biggest girls milk the cows, morning and night, and keep the barns clean. Old Nikolay mends ploughs, horse harnesses, pitchforks and scythes in his workshop. Anna Pushinka teaches Yelena and her friends how to get the honey from the beehives that are scattered through the orchards. I am in charge of collecting eggs. My friends Olga and Nina help. Olga and Nina are five, a year younger than me. They are twins and look exactly alike, except Nina’s nose is a little bit crooked from when she fell out of bed and squashed it sideways on the floor. The hens, ducks and geese wander free in the summer, so collecting eggs is like a treasure hunt and takes hours. Catching the hens for their daily hugs takes even longer, but I think it’s important because hugs make everyone happy and happy hens lay bigger eggs. Olga says I’m the best hen-hugger in all of Russia. Nina says I’ll be the best cow-hugger, too, when my arms grow longer. But good hugs have nothing to do with the size of your arms. It’s all to do with the size of your heart. When we are done with the hens, Olga, Nina and I can spend the rest of the day doing whatever we like. We climb the apricot trees, chase squirrels, lie in the meadow marvelling at how hot Ushanka’s black fur becomes in the sunshine, make daisy chains and race little boats of bark in the stream. I teach Olga and Nina the alphabet and we use charcoal to write our letters and our names all over the village – on doors and walls and the freshly cut ends of firewood. In between, I practise my knots. In case the German princemonsters return. I slip into Old Nikolay’s workshop and tie knots in the harnesses hanging on the walls. I wander into gardens where the washing is hung out to dry and tie knots in the laces on pants and smocks. I creep up behind Anna Pushinka and tie knots in her apron strings. I find baling twine in the hay shed and tie my own ankles together. I do such a good job of these last knots that I can’t get them undone. I have to jump all the way to Olga and Nina’s house and ask them to cut me free with their mama’s knife. At the end of each day, Ushanka and I run out into the distant barley fields to meet Mama. This is my favourite part of the day, because Mama always shouts, ‘Little Rabbit!’ and smothers my head with kisses. And as we walk home, we sing. Everyone – women, big boys and me. I love to sing. Almost as much as I love to be kissed by Mama. Sometimes one of the boys, Mikhail, has his balalaika with him. He takes the instrument out from beneath the sheaves of barley piled high on the wagon and plays music. We sing about forests and orchards and people who find their true love. As we walk home, arm in arm, my heart fills with happiness and my belly swells with pride that I am allowed to sing along with the big boys. And I can almost forget about the German prince-monsters and their lies about Russia and their big ugly boots. Almost. But today, when Mikhail reaches for his balalaika, I see other things hiding beneath the barley sheaves. Three of the mamas rush forward and cover them up, but it’s too late. I know they are there. I’ve already seen them. Rifles. Lots of rifles. Mikhail hugs his balalaika to his chest and blushes. ‘So play!’ cries Mama, her voice oddly loud and high. ‘Let’s play Sasha’s favourite song, “The Little Birch Tree”.’ So Mikhail plays and everyone sings about the lovely birch tree with its curly leaves and the branches that will be turned into silver flutes. They sing too quickly, too loudly, and as they sing and walk, they cast nervous sideways glances at me. ‘It’s alright,’ I say, when the song comes to an end. ‘I didn’t see the rifles.’ Mama nods and smiles, and I know it was the right thing to say. But I did see the rifles. And I think about Yelena wanting to get lots of guns and dynamite for the Partisans so they can shoot the Germans and blow them into thousands of tiny pieces, and Mama looking as though she agreed, and I know this is what the mamas and the big boys are doing. As well as harvesting, they are helping the Partisans. Three days later, I wake before dawn and I am all alone. Yelena is always here beside me when I wake. But not this morning. I climb down from our bed above the stove. Mama is filling a cloth sack with bread. She ties it closed with a piece of string and hands it to Yelena. ‘Stay out of sight,’ says Mama. ‘And don’t return until after dark.’ ‘Where’s she going?’ I ask. ‘Nowhere,’ snaps Mama. ‘Then why does she need all that bread?’ I ask. ‘There’s nothing left for us.’ Mama baked four loaves last night and she has stuffed them all into the sack. Yelena opens her mouth, but before she can speak, Mama shoves her out the door and sends her on the way to nowhere. Mama turns and stares at me, her blue, blue cornflower eyes wide with worry. ‘I know,’ I say, flopping down on the bench. ‘I didn’t see any bread.’ Mama sits beside me and takes my hand. ‘And . . .?’ she prods, obviously waiting for more. I puzzle for a while, then say, ‘And I don’t have a sister called Yelena.’ Mama laughs, softly and with a little bit of sadness around the edges. ‘Sweet Little Rabbit! You do have a sister called Yelena.’ ‘I do?’ I ask, now confused. ‘I haven’t seen the rifles or the bread, but I have seen Yelena?’ ‘Yes.’ Mama smiles and the magic makes me smile, too. And I am glad that Yelena is real because I love her very much. ‘Yelena is real,’ Mama explains, ‘but she does not carry sacks of bread into the forest for the Partisans.’ ‘Of course not!’ I shout, slapping my forehead. ‘Because there is no bread!’ Mama laughs loudly now, with not a hint of sadness. She hugs me, pressing me against her warm, loving heart, covering my head with kisses. ‘Clever Little Rabbit,’ she murmurs, and then, in barely a whisper, ‘Your papa would be so proud.’ When I wake the next morning, Yelena is sleeping beside me, her mouth open, her braided hair unravelling. Mama is serving kasha to a strange woman seated at our table. I crawl down from above the stove and slide along the bench beside her. I stare at her pants, her tunic, the rope she is using as a belt and her big boots. She’s dressed like a man! And there’s a rifle leaning against the wall near the door. ‘Hello,’ I say. ‘I’m Sasha.’ The woman doesn’t reply. She just shovels down her kasha. I line my four wooden bears along the table in front of her bowl and say, ‘These are my bears: Big Bear, Medium Bear, Little Bear and Even Littler Bear.’ ‘Hello, Sasha. Hello, bears.’ She smiles but she doesn’t tell me her name. ‘Why are you dressed like a man?’ I ask, tugging at the sleeve of her tunic. ‘Because men’s clothes make it easier to run and climb and crawl and shoot,’ she says. ‘You’re a Partisan!’ I gasp. ‘But she’s not real,’ says Mama, placing a bowl of kasha before me. ‘Is the kasha real?’ I ask. Mama laughs. ‘Yes, Little Rabbit.’ I’m glad the food is real, because I’m hungry. But I’m disappointed that the woman is not real. I was going to ask if I could use her rope-belt to tie her ankles together. For practice. But if she’s not real, then the rope and her ankles aren’t either. The woman finishes her kasha, hangs her rifle over her shoulder, kisses Mama on the cheek then slips out the door. I run to the window to watch her leave, but by the time I get there, she’s gone. Vanished. ‘Because she’s not real,’ I whisper. A week later, Mama and I are working in the garden. We sing as we weed between the flowers and pluck caterpillars from the vegetables. Anna Pushinka is picking strawberries in her garden and wanders over. ‘Taste these,’ she says, holding out the basket. Mama reaches in and takes out a fat strawberry and a tiny piece of folded paper. The strawberry goes into her mouth, the paper into her pocket. ‘What’s on the paper?’ I ask. ‘Paper?’ Anna Pushinka replies with a wave of her hand. ‘Goodness, Sasha! Who has money for paper? These are lean times. We must choose between paper for writing and noodles for our soup. And I always choose noodles.’ She chuckles and I know the paper is yet another thing that is not real. That night, Mama slips the paper to Yelena, but she drops it on the floor. I pick it up for her, and I see that there are tiny words and numbers written all over it. I wish I could read better. I’m desperate to know what it says. Or rather, what it doesn’t say, because it’s not real. Later, when Mama has tucked us into our bed above the stove and Ushanka has wrapped herself around the top of my head, I ask Yelena, ‘What’s on the paper?’ ‘What paper?’ says Yelena. ‘The paper that isn’t real,’ I reply. Yelena stares at me, nibbling her lip, then whispers, ‘A message for the Partisans. Stuff about where the Germans have their headquarters and when their trains are travelling and where they store their ammunition.’ ‘Why?’ ‘So the Partisans can blow them up.’ Yelena grabs my arm. ‘But don’t tell anyone. It’s a secret.’ ‘What’s a secret?’ I ask. ‘The message.’ ‘What message?’ I say, my eyes wide. Yelena laughs. ‘Good boy, Sasha.’ My belly swells with pride. I know how to play this game. ‘How are your knots coming along?’ asks Yelena. ‘Good! Yesterday, I crept into the dairy and tied knots in the apron strings of all the girls who were milking and only one of them noticed. Today, I tied Olga’s ankles together with Mama’s embroidery thread and just now, while you were taking a bath, I tied the sleeves of your blouse together in an enormous knot.’ Yelena rolls her eyes, then says, ‘I’ll see if I can find you some rope for practising.’ ‘Practising what?’ I ask. ‘Your knots,’ she says. ‘What knots?’ Yelena, my big sister who is twelve and always serious t
Present Continuous Tense Quiz Multiple Choice Questions Which sentence is in the present continuous tense? A) She sings beautifully. B) They are eating dinner now. C) He played the piano. D) I have finished my homework. Correct Answer: B Fill in the blank: "They __________ (to watch) a movie tonight." A) watches B) watched C) are watching D) is watching Correct Answer: C What does the present continuous tense usually express? A) General truths B) Habits C) Actions happening right now D) Completed actions Correct Answer: C Which sentence is NOT in the present continuous tense? A) I am meeting my friends later. B) She is studying for her exams. C) He reads a book every night. D) We are visiting our grandparents this weekend. Correct Answer: C Choose the correctly formed question in the present continuous tense. A) Do you going to the party? B) Are you go to the party? C) Are you going to the party? D) Is you going to the party? Correct Answer: C Fill-in-the-Blanks I __________ (to listen) to music right now. Answer: am listening She __________ (to not study) at the moment; she's watching TV. Answer: is not studying __________ (to be) they __________ (to play) soccer in the park? Answers: Are; playing The dog __________ (to bark) because it's hungry. Answer: is barking We __________ (to plan) our holiday; we can talk later. Answer: are planning Present Perfect Tense Quiz Multiple Choice Questions Which sentence is in the present perfect tense? A) They go to Spain every summer. B) She is going to the supermarket. C) I have seen that movie before. D) He reads the newspaper. Correct Answer: C Fill in the blank: "She __________ (to never, eat) sushi before." A) has never eaten B) is never eating C) never eats D) have never eaten Correct Answer: A What does the present perfect tense usually express? A) Actions happening right now B) Actions that have a connection with the present C) Regular habits D) Future plans Correct Answer: B Which sentence is NOT in the present perfect tense? A) I have just finished my homework. B) They have lived here for ten years. C) We are watching a new film. D) She has written three books. Correct Answer: C Choose the correctly formed question in the present perfect tense. A) Have you ever been to Italy? B) Do you ever been to Italy? C) Are you ever been to Italy? D) Is you ever been to Italy? Correct Answer: A Fill-in-the-Blanks They __________ (to not, see) the Eiffel Tower yet. Answer: have not seen I __________ (to read) three books this month. Answer: have read How many times __________ you __________ (to be) to London? Answers: have; been She __________ (to not, decide) on her major yet. Answer: has not decided We __________ (to travel) to three different countries since last year. Answer: have traveled
The following days are a jumble of gunfire, digging, gobbled food, soldiers running in and out of the forest in small groups, distant explosions, stray shells, bandaged heads and unexpected lulls. On the very first day, before dawn, I am ordered into one of the newly dug trenches. I huddle there, squeezing my magic buttons and singing songs to the dog. When the fighting stops, the dog disappears, but a new companion takes his place. A strange little soldier crawls along the trench toward me. ‘Private Sasha!’ he cries. ‘I’ve been looking for you all day long!’ He’s old, like a grandfather, a dedushka. He has a black patch over one eye, a tape measure around his neck and a row of pins threaded into his sleeve. Hanging from his belt is the most enormous pair of scissors I have ever seen and I wonder if he uses them as a weapon. He doesn’t tell me his name, so in my head he becomes Dedushka. Dedushka squats, cups his hand to his ear, peers over the top of the trench and smiles. ‘It’s safe to be upright . . . for now.’ He helps me to my feet, dusts me off and commands me to stand as tall and straight as I can. Then he measures me. Everything from head to toe – even my toes! He writes numbers in a little notebook, strings his tape measure back around his neck, salutes and hurries away. It’s all very strange, and I wonder if Dedushka has been bumped on the head during the battle and is now a little bit muddled. I should have given him a hug before he left. I chase after him but stop when I’m hit by a shovelful of flying dirt. Sleepy Bear is digging a cave! ‘Are you going to hibernate?’ I ask. Sleepy Bear chuckles. ‘No, although that would be wonderful! I could do with a lo-o-o-ong sleep.’ He sighs and closes his eyes. He doesn’t open them again and I realise that he has gone to sleep. Standing up! I shake his arm, and he opens his eyes and keeps talking. ‘No, I’m not hibernating. I’m digging a little nook where I can sleep and eat. I’ll hang up my raincape as a door that can open and close so it feels just like a real home . . . except for the lice . . . and the bad smells . . . and the bombs that make the walls shake and crumble.’ He points further along the trench to where other soldiers are digging. ‘We’re all making little houses in the ground.’ ‘Like rabbits and moles,’ I say. Sleepy Bear chuckles. ‘Yes! And soldiers who need to hide from German bullets and bombs.’ He stops digging to roll a cigarette. ‘Should I be making a house?’ I ask. ‘I want to hide from German bullets and bombs, too.’ Sleepy Bear flops to the ground, lights his cigarette, closes his eyes and takes a deep puff. I wait for him to answer, but, instead, he begins to snore! I poke him in the side. He snorts and he murmurs, ‘I think someone has already built you a house, Sasha. Keep going along this beautiful village street and you are sure to find it.’ He falls asleep once more. I kiss his dusty cheek and whisper, ‘Thank you, Sleepy Bear.’ A little way along, I see Cook in a cloud of smoke. He has lit a fire, right here in the middle of the trench, and is stirring a cauldron full of kasha. He squats as he stirs. ‘What are you doing?’ I ask. ‘Cooking supper, of course!’ he cries. ‘But why are you doing it here?’ Cook points his spoon at the ground above the trenches. ‘Because if I do it up there, my pot will be filled with holes from German bullets and all of the kasha will leak out onto the ground. It’s bad enough that our supplies can’t get through German lines and there’s nothing to cook but buckwheat for kasha. But if we lost the kasha, too . . .’ ‘Hungry soldiers,’ I say. Cook nods. ‘And grumpy!’ ‘Like Boris!’ I gasp. ‘Even worse,’ warns Cook. I picture the kasha pot full of bullet holes. And then I realise that if the kasha pot were full of holes, then Cook would be, too. I wrap my arms around Cook’s neck and say, ‘I think this is a very good place for cooking our supper.’ I kiss his smoky cheek and run along. At the end of the trench, I find the biggest hole of all. It’s wide and deep and as busy as a beehive in a blossom tree. Above, a group of soldiers is rolling logs into place for a roof, while below, typewriters rattle and pencils scratch and papers flutter and voices crackle out of five different radios. Their words tangle together to tell a strange wartime fairy tale about German guns and a loving father called Stalin and a Red Army regiment that is lost in the deep, dark forest and a wicked beast called Hitler and a delivery of vegetables that was hit by a bomb and blown into a million tiny pieces too small even to make soup. In the middle of it all, wrestling with a rumpled map, his rifle still slung over his shoulder, is Major Scruff. ‘Major Scruff!’ I run and jump into his arms. ‘Is this our new home?’ ‘Yes, Sasha. I suppose it is.’ ‘Is it safe from German bullets and bombs?’ I ask. He stares at me. ‘Were you scared in the trenches today, Sasha?’ ‘No,’ I reply. ‘I had magic buttons and a dog and some songs to sing. Were you scared in the forest, Major Scruff?’ ‘Yes,’ he says. ‘Poor Major Scruff!’ I press my hand against his cheek. The dark, rough stubble is grubby with grit and his eyelids are taking a long time to open after every blink. ‘You need a shave and a nap!’ I scold. He chuckles. ‘I am too tired to shave and too busy to nap.’ I scrunch my nose while I consider his problem. ‘I know!’ I cry. ‘You nap and I will shave your whiskers. That will be two jobs tumbled into one!’ And so that’s what we do. Major Scruff slumps into a chair and snoozes while I lather his face with soapy water and shave his whiskers. The soap suds travel from his face, up into his hair and down the front of his uniform, and I have to shave his jaw and chin three times because I keep missing bits, but I finally get it all done. I am just wiping his cheeks dry when the dog appears. He licks my hand, then stretches up and licks soap suds from Major Scruff’s ear. Major Scruff wakes with a start. He feels his newly shaved face and cries, ‘Wonderful, Sasha! I feel smooth, clean, rested and ready for action.’ He ruffles my hair. ‘We must do this again tomorrow. Although next time, you might wake me with a gentle shake of the shoulder instead of licking my ear.’