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Sheldon Cooper

Preliminary studies showed that identified cortically-projecting BF GABA neurons are excited by neurotransmitters promoting cortical activation acetylcholine, norepinephrine, histamine, orexins , likely accounting for their faster firing rate during waking and REM sleep Rostral and caudal PV GABAergic projection neurons synapse onto hippocampal and neocortical PV-positive neurons which control hippocampal and cortical gamma rhythms, respectively see sect. Other subpopulations of BF GABA neurons that are likely sleep related project to the thalamic reticular nucleus 49 and lateral hypothalamus However, VTA GABA neurons increased their firing prior to intracranial self-stimulation of the medial forebrain bundle, indicating that they may be involved in the attentive processes related to brain reward GABAergic medium spiny neurons in the striatum receive a massive glutamatergic cortical input and control the activity of thalamocortical neurons.

Transitions from NREM sleep to wakefulness convert the firing of striatal neurons from fast cyclic firing, synchronized with cortical field potentials, to an irregular pattern of action potentials triggered by disorganized depolarizing synaptic events of variable amplitude Improved function in minimally conscious patients produced by stimulation of the nonspecific thalamic nuclei may be mediated by increased cortico-striatal-thalamic interplay In addition, the BF , claustrum, amygdala, VTA, laterodorsal tegmentum, and hypothalamus provide minor glutamatergic projections to the cortex.

Vesicular glutamate transporters are expressed in cortically projecting orexin neurons in the perifornical hypothalamus and serotonergic DRN neurons , suggesting that glutamate is a cotransmitter in these neurons. Furthermore, glutamate is the major neurotransmitter released from rostral midbrain brain stem reticular formation neurons projecting to the thalamus. Dissociative anesthetic agents such as ketamine inhibit glutamatergic NMDA receptors, whereas pharmacological agents that prolong the decay of AMPA receptor currents AMPAkines are proposed to enhance attention and cognition.

The thalamus is an important component of the dorsal branch of the ARAS involving the nonspecific thalamic nuclei FIGURE 5 , as well as the specific relay nuclei which convey external sensory information to the cortex. EEG rhythms typical of wakefulness are sculpted through interactions between the thalamocortical relay neurons, corticothalamic pyramidal neurons, and GABAergic neurons in the thalamic reticular nucleus.

At the onset of conscious states i. In a thalamocortical slice preparation, coincident stimulation of nonspecific thalamic nuclei centrolateral intralaminar nucleus or direct stimulation of layer I together with relay nucleus stimulation induced supralinear summation of the two inputs in cortical output layer V, providing a possible mechanism by which the nonspecific nuclei promote arousal The effector systems used by the neurotransmitter systems involved in generation of wakefulness have been studied by in vitro electrophysiology, pharmacology, and genetic methods see sect.

In addition, effects on other intrinsic membrane currents contribute to the activation of thalamocortical and limbic neurons , Studies involving stimulation of the brain areas and neurotransmitter systems comprising the ARAS consistently report EEG activation and wakefulness as a result.

These studies include both older techniques of electrical stimulation or infusion of pharmacological agents as well as state-of-the-art optogenetic techniques where light-activated ion channels are introduced into the desired neuronal population by genetic engineering techniques 6 , In contrast to the stimulation experiments, studies where localized inactivation of individual neurotransmitter systems or nuclei of the ARAS have been performed summarized in TABLE 1 generally produce relatively minor changes in cortical EEG or the amount of wakefulness in a h period see sect.

II C , with the possible exception of the parabrachial nucleus see sect. There are several possible explanations for this dichotomy between stimulation and inactivation experiments. First, the ARAS systems are strongly interconnected, mutually excitatory to each other FIGURE 6 and converge onto common effector systems at the level of thalamic and cortical neurons , Thus there is considerable redundancy in the system, and inactivation of any individual component of the system is compensated for by the other systems.

This is perhaps not surprising considering the enormous adaptive advantage of wakefulness! A second possibility for the mild effects of loss-of-function experiments is that the systems so far targeted are not absolutely required for wakefulness. The majority of studies have focused on neuromodulatory systems, whereas selective inactivation of glutamatergic and GABAergic systems projecting to the neocortex have not been tested due to technical difficulties in targeting these systems. The neuromodulatory systems are clearly able to generate cortical activation when stimulated but may only be required for specific aspects of wakefulness.

Specific roles for these systems could be 1 facilitation of LVFA acetylcholine ; 2 inhibition of sleep-active neurons norepinephrine, serotonin, acetylcholine; see sect. III ; 3 maintenance of high muscle tone norepinephrine during waking see sect. IV A ; 4 consolidation of wake periods orexins ; 5 maintenance of waking in a novel environment histamine ; 6 enhanced arousal in the presence of rewarding stimuli dopamine, acetylcholine ; 7 enhanced arousal in the presence of aversive stimuli norepinephrine, serotonin, histamine ; and 8 consolidation of memories through enhancement of synaptic plasticity acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexins.

Methods to selectively stimulate these systems e. This section describes the mechanisms underlying the EEG signs of NREM sleep also called slow-wave sleep and the mechanisms that cause the circadian and homeostatic inhibition of wake-promoting ARAS neurons. Stage 1 NREM sleep exhibits theta activity at frontal sites and alpha activity posteriorally, similar to drowsy waking sect.

The cortical slow oscillation 0. NREM sleep is also characterized by low skeletal muscle tone and slow, rolling eye movements. Here we first describe phasic events occurring during NREM sleep in the thalamocortical system spindles and hippocampal formation sharp wave-ripple complexes and then discuss the delta and slow oscillations typical of deep NREM sleep. K-complexes represent a combination of one cycle of the neocortical slow oscillation followed by a spindle in thalamocortical neurons 27 , 28 , Although the thalamic reticular nucleus is the generator of spindles, in intact animals spindles are initiated and terminated in concert with delta and slow oscillations in corticothalamic and thalamocortical neurons due to the extensive interconnections of these cells As aminergic inputs are slowly withdrawn during early NREM sleep, long-lasting 50 ms bursts of action potentials are generated in reticular nucleus neurons due to activation of low-threshold T-type calcium channels.

These channels are of the Ca v 3. Bursts at spindle frequencies lead to large and long-lasting inhibitory synaptic potentials IPSPs in thalamocortical neurons which remove the inactivation of T-type Ca v 3. Thus, at the offset of the IPSPs, when the cell becomes more depolarized, the low-threshold calcium channels are activated, calcium enters the cell, resulting in a low-threshold calcium spike crowned by a short 5—15 ms burst of sodium-dependent action potentials in the thalamocortical neurons.

This burst in thalamocortical neurons leads to EPSPs in cortical neurons and to action potentials which together make up the spindle recorded in the EEG. Synchronization of spindles is achieved via recurrent inhibitory and electrical synaptic connections between thalamic reticular neurons Spindles can also be recorded in cortical projection sites such as the basal ganglia , possibly providing a substrate for procedural learning during sleep. Spindles decline during deep sleep due to the increased hyperpolarization of thalamocortical relay neurons but may reappear just prior to the transition to REM sleep when thalamocortical relay neurons become more depolarized again due to increased ascending brain stem excitation.

In vivo, extracellular and intracellular recording studies revealed that thalamic reticular neurons fire tonically during waking and switch to burst firing during NREM sleep, similar to thalamocortical relay neurons , The mechanism underlying inhibition of spindle activity during REM sleep is less clear but has been proposed to be due to input from REM-on cholinergic neurons which hyperpolarize thalamic reticular neurons via a muscarinic M 2 receptor mediated inhibition of leak potassium conductance , High-frequency — Hz field potentials termed sharp wave-ripple complexes can be recorded in the hippocampus and associated areas during quiet wakefulness and NREM sleep in rodents , , and in humans When released from inhibition, the synchronized firing of CA3 pyramidal neurons leads to a concerted activation of Schaffer-collateral synapses in the CA1 region and subsequently of subicular and downstream retrohippocampal cortical structures Feed-forward and feedback activation of hippocampal GABAergic interneurons leads to a high-frequency oscillation in the membrane potential of pyramidal neurons due to IPSPs, reflected as a high-frequency ripple in the extracellular potential Phase-locked interneurons fire at high frequencies on every cycle of the extracellularly recorded oscillation and entrain the firing of pyramidal neurons, which fire at lower frequencies , Accordingly, ripple frequency is reduced by pharmacological prolongation of GABA A receptor-mediated currents Surprisingly, ripple amplitude and entrainment of pyramidal neurons were increased in mice lacking the GluR1 subunit of AMPA-type glutamatergic receptors specifically on PV-positive interneurons, possibly as a result of developmental compensation Modeling studies suggest that electrical coupling between the axons of pyramidal neurons is required to synchronize their activity In support of this idea, the occurrence of ripples in vitro was reduced in mice lacking one type of gap junction protein connexin 36 , and the intraripple frequency was reduced However, in another report, the occurrence of in vitro kainate-induced sharp waves was actually increased in these mice Delta oscillations are best understood at the thalamic level.

Recordings in vivo from thalamocortical neurons revealed that stereotyped high-frequency bursts of action potentials occur at delta frequencies interspersed with silent periods 25 , , , , , a pattern which can be abolished by brain stem cholinergic stimulation or by increases in ambient light 25 , , The ability of thalamocortical neurons to generate burst firing in the delta frequency range is due to their intrinsic membrane properties , , , , Hyperpolarization resulting from the activation of calcium-dependent potassium conductances after a burst of action potentials or from inhibitory synaptic inputs leads to the opening of hyperpolarization-activated, cAMP-modulated cation HCN channels causing the so-called H-current I h.

This slowly activating current provides a depolarizing drive towards the threshold for action potentials and is a major contributor to the duration of the interburst interval , I h is modulated during waking by activation of neurotransmitter receptors coupled to stimulation of cAMP e. As well as activating I h , hyperpolarizations result in deinactivation of low-threshold calcium channels, allowing their subsequent activation once the membrane potential reaches less negative potentials Opening of these calcium channels leads to a low-threshold spike LTS and a burst of action potentials — Bursts of action potentials in thalamocortical neurons lead to a prominent burst in large numbers of cortical pyramidal neurons.

Bursting of corticothalamic neurons potentiates intrinsic rhythms in thalamocortical neurons and entrains their firing through excitation of thalamic reticular neurons leading to rhythmic hyperpolarizations in thalamocortical neurons, creating increased network synchronization 25 , Calcium influx through the low-threshold channels allows activation of calcium-dependent potassium conductances, restarting the cycle.

Ascending influences during waking or REM sleep block this cycle by acting on PLC-coupled receptors that block a leak potassium conductance causing inactivation of the low-threshold calcium channels and bringing the membrane potential out of the range of the H-current , Low-threshold bursts in thalamocortical neurons were abolished in mice constitutively lacking the Ca v 3.

Delta waves were abolished in these mice with knockouts in the whole brain or thalamus, whereas deletions of Ca v 3. Loss of delta waves was associated with fragmented sleep with a higher incidence of brief arousals. Similar to thalamocortical neurons, bursting in thalamic reticular neurons is regulated by calcium dynamics involving low-threshold calcium channels, endoplasmic reticulum calcium ATPases which sequester intracellular calcium, and small-conductance calcium-dependent potassium SK channels Like Ca v 3.

This phenomenon, discovered by Steriade in anesthetized cats , was subsequently observed in naturally sleeping animals 28 , , and in humans 27 , Somewhat confusingly, despite its name, the so-called slow oscillation does not necessarily imply rhythmicity. High-density EEG recordings in humans revealed that each cycle of the slow oscillation represents a traveling wave originating most frequently in prefrontal-orbitofrontal regions and propagating towards more posterior cortical areas Slow-wave activity SWA; 0. Periods of sleep deprivation cause increases of SWA in the subsequent sleep period in both animals and in humans.

SWA is highest at the beginning of the sleep period and progressively decreases during sleep. Naps during the day also reduce SWA in the subsequent night The slow oscillation is generated within the cortex since it is abolished in thalamic neurons following removal of the cortex , and it persists following disconnection of subcortical inputs and can occur in vitro in cortical slices, following manipulation of the ionic milieu bathing the slices , However, in intact animals, the slow oscillation strongly influences the activity of the thalamus through corticothalamic projections and conversely the thalamus influences the cortex through thalamocortical projections , , , Intracellular recordings from cortical neurons in vivo , and in vitro revealed that the slow oscillation consists of prolonged depolarizations associated with extracellular gamma frequency activity UP states separated by prolonged hyperpolarizations DOWN states when most cortical neurons are silent , These states are well-synchronized over widespread areas of cortex Consistent with this idea, the frequency and amplitude of miniature excitatory postsynaptic currents in pyramidal neurons of frontal cortex was enhanced following waking and decreased following sleep The hyperpolarizing phase is due to withdrawal of excitatory input.

Many of the sleep-active neurons in the medial and lateral preoptic area are also temperature sensitive, likely explaining the coupling of body temperature and sleep In the BF, caudally projecting, possibly sleep-active, GABA neurons are intermingled with cortically projecting cholinergic, GABAergic, and glutamatergic neurons which increase firing in association with cortical activation With the use of Fos immunohistochemistry to identify neurons that had been recently active, a cluster of sleep-active neurons was identified in the ventrolateral preoptic nucleus VLPO FIGURE 2 of the rat These neurons contained the inhibitory neurotransmitters GABA and galanin and projected heavily to nuclei of the ARAS, especially the histaminergic tuberomammillary nucleus , , , Single-unit recordings targeting this area confirmed that it contains sleep-active neurons Extensive neurotoxic lesions of the central cluster of the VLPO in the rat led to a large decrease in delta power and NREM sleep time and a fragmentation of the sleep-wake cycle , effects which persisted for at least 3 wk postlesion.

All of these were inhibited by norepinephrine and acetylcholine, and the majority were also inhibited by serotonin 5-HT 1A Initial experiments suggested that histamine and orexin did not affect the firing rate of VLPO neurons, but more recent experiments have revealed an indirect histaminergic inhibition due to excitation of local inhibitory interneurons Retrograde tracing revealed surprisingly few cholinergic projections to VLPO but prominent projections from the histaminergic tuberomammillary nucleus, norepinephrine neurons in the LC and ventrolateral medulla, and serotonergic neurons in the dorsal median and central linear raphe nuclei Interestingly, VLPO neurons also receive direct inputs from the retina and indirect projections from the suprachiasmatic nucleus via the dorsomedial hypothalamus , , , one pathway by which light exposure could affect sleep.

In vitro studies also revealed that VLPO neurons are excited by adenosine through an indirect mechanism: A 1 receptor-mediated presynaptic inhibition of inhibitory synaptic inputs , In addition, activation of adenosine A 2a receptors by infusion of an A 2a agonist in the subarachnoid space underlying the VLPO area increases the activity of VLPO neurons in vivo On the other hand, high-frequency electrical stimulation or perfusion with glutamate or the GABA A receptor antagonist bicuculline enhanced NREM sleep and inhibited the activity of wake-active neurons in the perifornical hypothalamus Experiments comparing the extent of Fos during spontaneous sleep, sleep deprivation, and recovery from sleep deprivation suggest that MnPO neurons are active during sleep deprivation, whereas VLPO neurons are mainly active during sleep , , Thus MnPO neurons increase their activity in response to increased homeostatic sleep pressure, whereas VLPO neurons may function to consolidate and maintain sleep and regulate sleep depth Von Economo was the first to propose the existence of an anterior hypothalamic sleep-promoting area and a posterior hypothalamic waking center.

More recent anatomical tracing experiments revealed that neurons in the core of the VLPO project heavily to wake-promoting histamine neurons in the tuberomammillary nucleus TMN of the posterior hypothalamus and also to wake-promoting serotonin DRN neurons and norepinephrine LC neurons in the brain stem A crucial aspect of this model is that the two halves of the switch, by strongly inhibiting each other, create a feedback loop that is stable in only two states such that intermediate states of sleep and wakefulness are very brief.

A further component to the model was the proposal that orexins stabilize behavioral state via their strong excitatory actions on wake-promoting neurons. Analysis of orexin knockout mice revealed that they have many more transitions between wake, NREM, and REM states than do wild-type mice, supporting this model Although intuitively appealing, this model has a few weaknesses. First, the model does not well represent the changes in firing of all the neuronal subpopulations involved. While sleep-active preoptic neurons have fast transitions around state-transitions , the firing rate of wake-active BF neurons changes more slowly and thus more closely resembles a latch than a switch.

Second, the mechanism responsible for turning the switch on and off is unclear since a switch remains in one state unless a third mechanism causes a transition. Possible candidates for facilitators of the wake-sleep transition are sleep homeostatic factors that slowly build up during wakefulness and are discussed in the following section. Figure 7. Transitions between wake and sleep are due to mutual inhibition between these sleep- and wake-related nuclei.

Adapted from Saper et al. Nature —, , with permission from MacMillan Publishers Ltd. Homeostatic control of sleep refers to the increased propensity for sleep during prolonged waking and the prolonged sleep time and depth of sleep reflected as increased EEG slow wave activity following a period of sleep deprivation , Sleep homeostasis is considered to reflect the accumulation of sleep homeostatic factors during waking, particularly in the BF and cortex, in a manner related to brain energy usage see sect. III D. Sleep homeostatic factors inhibit the activity of ARAS neurons as well as cortical neurons and thereby facilitate the slow oscillations typical of NREM sleep.

The search for sleep-promoting factors dates back years when Ishimori and Legendre and Pieron reported that injection of CSF from a sleep-deprived dog into the cisterna magna of a normal animal induced sleep. Later in , Pappenheimer et al. These pioneering studies suggested that endogenous humoral factors are induced and accumulate during waking and generate a homeostatic sleep response. This led to a series of investigations in search of humoral sleep-promoting substances , leading to the identification of several substances including 1 delta sleep inducing peptide ; 2 uridine ; 3 oxidized glutathione, originally designated as SPS-B ; 4 muramyl dipeptide N -acetylmuramyl- l -alanyl- d -isoglutamine , originally described as Factor S ; and 5 prostaglandin D 2 In the following years, a variety of additional endogenous sleep-inducing substances were identified including peptides, growth factors, and cytokines as well as neuromodulators such as adenosine and NO.

Homeostatic sleep factors should fulfill the following criteria: 1 administration of the substance induces sleep; 2 the levels of the substance in the brain should increase with increasing sleep propensity; and 3 the substance should act on brain regions and neurons involved in the regulation of sleep or wakefulness. Recent studies have focused extensively on the role of adenosine, nitric oxide, prostaglandin D 2 , and cytokines in sleep regulation and the following sections will review the latest research on these factors.

The neuromodulator adenosine links energy metabolism, neuronal activity, and sleep 79 , 91 , , The hypnogenic effects of adenosine were first described in cats by Feldberg and Sherwood and later in dogs by Haulica et al. Systemic and central administrations of adenosine or adenosine A 1 receptor agonists induced sleepiness and impaired vigilance 91 , , , , , , by inhibition of wake-active neurons.

Adenosine A 2A receptors are also implicated in mediating the somnogenic effects of adenosine by excitation of sleep active neurons , , Stimulants such as caffeine and theophylline counteract the sleep-inducing effects of adenosine by serving as antagonists at both A 1 and A 2A adenosine receptors , Adenosine levels correlate with time spent awake. Endogenous, extracellular adenosine levels in the BF , , , , and cortex , increase in proportion with time spent awake FIGURE 8. Thus adenosine induces sleep and adenosine levels track sleep need, fulfilling the criteria for adenosine being a homeostatic sleep factor.

Measurements of extracellular adenosine levels across the sleep-wake cycle and in response to sleep deprivation revealed that adenosine levels rise only in select regions of the brain , In particular, adenosine levels correlate with time awake in the region of the caudal BF containing cortically projecting wake-active neurons, and in the cortex itself. In contrast, adenosine levels did not follow this pattern in other brain areas such as the preoptic area of the hypothalamus, ventral thalamus, DRN, or pedunculopontine tegmentum.

BF adenosine levels also rise when rats are exposed to a sleep fragmentation protocol , possibly explaining excessive daytime sleepiness in sleep disorders where sleep is fragmented see sect. Figure 8. Investigations of the role of adenosine AD as a neuromodulatory sleep factor. A : extracellular AD concentrations in the feline basal forebrain BF for min consecutive samples from an individual animal, showing elevated levels during wakefulness.

Reprinted with permission from AAAS. AD levels are significantly elevated by hour 2 of SD and remain elevated until recovery sleep, when levels fall towards baseline levels. Levels are normalized to baseline levels in the 2 h preceding SD. This signaling cascade appears to be confined to cholinergic neurons of BF.

Adapted from Basheer et al. Neuroscience —, , with permission from Elsevier. I Mechanisms underlying adenosine increases during wakefulness. Increased levels of extracellular adenosine during prolonged wakefulness are caused by interactions between neuronal and glial mechanisms. Glutamatergic stimulation of the BF elevates extracellular adenosine and increases sleep Selective activation of glutamatergic NMDA receptors on hippocampal pyramidal or on brain stem cholinergic neurons also leads to slow adenosine release and inhibition of neuronal activity.

In the BF, cell-specific lesion of cholinergic neurons attenuates the sleep deprivation-induced increase of adenosine , , suggesting either that increases in extracellular adenosine are derived from these neurons or that they release an essential signal for extracellular adenosine accumulation. Such a signal may be NO see next section. In turn, breakdown of the extracellular ATP released by glia yields adenosine, which depresses neuronal activity , Blockade of vesicular release via transgenic expression of a dominant-negative SNARE domain specifically in astrocytes dn-SNARE mice blocked the accumulation of homeostatic sleep pressure following sleep deprivation as reflected by slow-wave activity and prevented the sleep-suppressing effects of an adenosine A 1 receptor antagonist , , suggesting that blocking gliotransmission affected sleep by reducing the accumulation of extracellular adenosine.

Electrophysiological, behavioral, and molecular evidence suggest that in wake-active areas, the effects of adenosine are primarily mediated via A 1 receptors. A weaker postsynaptic inhibitory effect mediated via an A 1 receptor-mediated shift of the activation threshold of the hyperpolarization-activated current I h is observed in thalamic relay neurons and BF noncholinergic neurons Adenosine further dampens neuronal activity and promotes sleep via presynaptic inhibitory effects on excitatory glutamatergic inputs to cortical glutamatergic neurons and wake-active cholinergic 48 , , , and orexin neurons, as well as on inhibitory GABAergic inputs to sleep-active VLPO neurons , Infusion of A 1 receptor agonists in the BF, laterodorsal tegmentum, lateral hypothalamus, and prefrontal cortex increases sleep, whereas infusion of A 1 receptor antagonists in the same areas increases waking 14 , , , , , Although adenosine A 1 receptors have effects in multiple regions of the brain controlling sleep-wakefulness, as mentioned above, to date adenosine levels have only been shown to increase with prolonged wakefulness in the BF and neocortex.

Consistent with the BF being a crucial site mediating adenosine effects, local perfusion of an A 1 receptor antagonist in this region activated wake-active neurons 17 , , and localized suppression of A 1 receptor expression using antisense oligonucleotides significantly reduced spontaneous sleep time as well as the homeostatic sleep response In contrast, adenosine A 1 receptor blockade in the lateral hypothalamus did not block the homeostatic sleep response While sleep homeostasis was intact in constitutive A 1 receptor knockout mice , conditional deletion of A 1 receptor in forebrain and brain stem after 6—8 wk of age, circumventing developmental compensation, not only resulted in a decreased homeostatic sleep response after sleep restriction but also led to a failure in working memory consolidation sect.

Prolonged sleep deprivation upregulates A 1 receptor mRNA and protein in BF and cortex in both rats and humans 74 , 76 , , Upregulation of adenosine receptors provides an additional level of homeostatic control beyond rises in extracellular adenosine levels. Increased stimulation of the A 1 receptor during sleep deprivation activates the PLC pathway, mobilizing intracellular calcium which in turn activates the transcription factor NF-kB and upregulates A 1 receptor expression 73 , What is the involvement of the adenosine A 2A receptor in the homeostatic sleep response of adenosine?

A 2A receptors are coupled to the stimulatory G s subunit and activate adenylyl cyclase. In contrast to the A 1 receptor with its wide distribution in brain, the distribution of A 2A receptor is more restricted to basal ganglia structures such as striatum, nucleus accumbens, and olfactory tubercle with much lower abundance in other areas such as the hippocampus, neocortex, BF, and other sleep-wake regulatory structures Consistent with this are the observations that adenosine excites one subpopulation of sleep-promoting VLPO neurons via A 2A receptors , and administration of CGS into the lateral preoptic area close to the VLPO induces sleep In A 2A receptor knockout mice, the homeostatic sleep response following sleep deprivation and the wake-promoting effects of caffeine were blocked , although given the strong expression of this receptor in the basal ganglia, effects on motivation or motor behavior may confound these results.

Accordingly, the locomotor stimulatory effects of caffeine mediated via A 2A receptor blockade were shown to require the presence of A 2A receptors in the nucleus accumbens The importance of adenosine as a sleep factor is supported by studies of enzymes involved in adenosine metabolism. Adenosine deaminase is involved in clearance of adenosine from the extracellular space.

Blocking its activity using coformycin increased extracellular adenosine and sleep The enzyme adenosine kinase phosphorylates adenosine to adenosine monophosphate, and blocking adenosine kinase activity with ABT increased sleep in rat These data from rats are consistent with findings in mice that a genomic region encoding adenosine deaminase influences the rate at which NREM sleep need accumulates during wakefulness sect.

VI In humans, a genetic variation of the adenosine deaminase gene resulting in an amino acid substitution asparagine for aspartic acid results in decreased enzyme activity and is associated with increased sleep time and sleep intensity , NO is a small gaseous molecule with multiple roles in the control of sleep and wakefulness see also sects.

II and IV. The enzymatic activity of NOS is highest in the rat brain when animals are awake 57 , and NO itself is detected in higher quantities in the cortex during waking Systemic or intracerebroventricular icv administration of NOS inhibitors at light onset reduced NREM sleep within the first few hours in rats , , , , , , and in rabbits Currently, the cellular signaling pathway by which sleep deprivation leads to the induction of iNOS is unknown.

NO has multiple cellular effectors, but one which may be particularly important in the context of the homeostatic sleep drive is release of adenosine FIGURE 8. In vitro studies in culture and brain slices have shown that NO donors cause release of adenosine, which in turn inhibits neuronal activity , , In vivo, NO production and adenosine increased concurrently in the BF during sleep deprivation , Recent in vitro electrophysiological evidence suggests that NO causes an initial excitation of cholinergic and cortically projecting GABAergic BF neurons which is followed by a long-lasting inhibition that can be reversed with an adenosine A 1 receptor antagonist, suggesting mediation by adenosine Similarly, in vivo, the effects of NO donors on BF neurons were found to be dose-dependent, with lower doses favoring excitation and higher doses leading to more inhibition , Similar mechanisms may also be active in the perifornical lateral hypothalamus The presence of nNOS has been recently described in a small subset of cortical interneurons which are sleep active as determined by Fos immunohistochemistry , In rats, mice, or hamsters, a majority of cortical GABAergic interneurons that express nNOS also express Fos during the recovery sleep that follows sleep deprivation.

Fos expression in these sleep-active, nNOS-immunoreactive neurons parallels changes in the intensity of slow-wave activity in the EEG, and thus these neurons are suggested to be part of the neurobiological substrate that underlies homeostatic sleep regulation , , Prostaglandins are lipid signaling molecules produced from arachidonic acid through the cyclooxygenase pathway. The most abundant prostanoid in the brain, prostaglandin D 2 PGD 2 , meets all the criteria of a potent sleep-factor , , Infusion of PGD 2 into the third ventricle or preoptic area of rats , , or the third ventricle of monkeys increased sleep in a dose-dependent manner.

Further investigations in rats showed that the levels of PGD 2 in CSF increase with increasing time awake and propensity to sleep , Lipocalin-type prostaglandin synthase L-PGDS is expressed in the brain and has been associated with sleep-wake regulation The activation of DP 1 R by PGD 2 in the meninges is followed by an increase in adenosine that acts on the A 2A receptor in the sleep promoting preoptic area The role of adenosine in the leptomeninges has been demonstrated by infusion of A 2A selective agonist CGS , leading to increased Fos expression in VLPO and increased sleep , Like adenosine, PGD 2 is implicated in the homeostatic sleep response as animals that lack L-PDGS or PGD2 receptors fail to exhibit a sleep rebound in response to sleep deprivation , and infusion of PGD 2 mimics the effects of prolonged wakefulness in promoting sleep Clinical data suggest that the PGD 2 -A 2A sleep inducing system may be particularly important in mediating enhanced sleep in pathological states.

Cytokines are best known for their role in the immune system response to infection which includes enhanced sleep Several cytokines and their receptors are present in the brain, and even in the absence of immune challenge, they are involved in sleep regulation , Administration of either of these cytokines increases NREM sleep in mice, rats, rabbits, cats, and sheep , , , In humans, IL-1 administration results in fatigue and sleepiness , , , In cat cerebrospinal fluid, the changes in ILlike activity correspond to sleep-wake behavior In humans, plasma concentrations of IL-1 peak at sleep onset The mRNA levels of these cytokines increase during sleep deprivation However, he no longer preoccupies his time with investigating why the predicted mass of the quantum vacuum has little effect on the expansion of the universe.

Sheldon has redirected his work to the nature of dark matter. In addition to studying the WIMP model of dark matter , a particle physics point of view, he also considered the scalar-field model of dark matter , a large-scale geometric point of view. This led him to attempt a full proof of the Penrose Conjecture.

Bridging theory and experiment, Sheldon is active in the field of particle physics phenomenology at high-energy colliders such as the LHC. Sheldon came close to figuring out why the Large Hadron Collider had yet to isolate the Higgs boson particle. Though, he was refused clearance for a very prestigious government research fellowship at a secret military supercollider , located beneath a fake agricultural station In a similar capacity, Sheldon has made advances in theoretical plasma physics , studying turbulence and how it might be reduced to improve fusion reactor designs.

Consequently, Sheldon worked with colleague Barry Kripke on the grant proposal for a new fusion reactor , as the university was only allowed to submit one proposal. From nuclear theoretic calculations, he was thought to have discovered a method for synthesizing a new stable superheavy element.

Despite the fact that a Chinese research team at the Hubei Institute for Nuclear Physics ran a test on a cyclotron with extremely promising results and reportedly found the element, his calculations were wrong — the table from the Handbook of Chemistry and Physics in which he looked up the reaction rates of elements such as mendelevium , was in units of square centimeters cm 2 , which he misread as square meters m 2 , meaning he was off by a factor of 10, Sheldon surmised there must be some resonance between the elements he did not consider.

In fact, someone from the Chinese research team added simulated signals to the data files, as Leonard Hofstadter re-ran the tests in his lab and disproved Sheldon's theory. Sheldon additionally engages in condensed matter physics research on occasion and has lectured on topological insulators , as well as given a seminar on thermodynamic fluctuations.

He discovered that electrons travelling through a graphene sheet on hexagonal pathways possess zero effective mass since they coincidentally exhibit the same dispersion pattern as fermions and must be considered as a wave. In addition, he had a minor epiphany regarding the polymer degradation phenomenon.

From a philosophical perspective , Sheldon has grappled with Gedankenexperiments i. He produced four out of the five Gedankenexperiments he thought necessary for a cogent restatement of the quantum measurement problem, before the information was lost. For his contributions to theoretical physics , he won a Caltech Chancellor's Award for Science.

In the experiment, he detected what he believed was a significant monopolar magnetic charge , validating one of the chief predictions of superstring theory. Though Sheldon publicly announced he had confirmed string theory and would receive a Nobel Prize, he learned that the charge detected was actually static electricity from the others' electric can opener, forcing Sheldon to issue a retraction to his announcement and severely damaging his reputation at the university. Soon after, National Public Radio with Ira Flatow from Science Friday interviewed him by phone from his office , regarding the recent so-called discovery of magnetic monopoles in spin ices.

Based on his supposed discovery of a new stable superheavy element — which was actually a blunder — Sheldon appeared on Science Friday twice wherein a possible Nobel Prize in Chemistry was mentioned, had an article written about him in Physics Today and the National Science Foundation NSF wanted to give him a substantial grant. The paper was well received by the scientific community that included Professor Stephen Hawking. In " The Anxiety Optimization ", Sheldon is trying to increase his working efficiency by keeping a high anxiety level while driving everybody crazy.

The only good point is that he wants his friends to annoy him. Extremely tired, both Penny and Leonard put him to bed singing " Soft Kitty ". Leonard gets an idea to compare the universe to the surface of an Nth dimension sphere which he describes to Sheldon who finds the theory interesting. He works out he math. Together they are praised, lecture on their discovery and get an award. Howard comes up with the idea to turn it into a working guidance system which is patented and Howard builds a working prototype by the end of season 9.

In the 11th and 12th seasons, Sheldon and Amy work together on a Super-Asymmetry for string theory which is published and widely applauded. After a couple of Fermi-Lab scientists accidently prove their theory, all of the are in competition for a possible Nobel Prize. Leonard locates an emergency VHS tape made by him when he was eleven.

His character from " Young Sheldon " tires to give him a pep talk, but it was recorded over by his father with one of his football games. Amy keeps watching it and then finds his fathers halftime pep talk which does help Sheldon. They can learn from failure as much as they can learn from success. Sheldon is encouraged and even thanks his dead father in the end. At the ceremony Sheldon puts aside his self-centered speech and realizes that his achievement isn't just his, but also his family and friends who encouraged him and tolerated him.

Sheldon introduces his friends to the world and tells them how much he loves them. Aside from his characteristic idiosyncrasies, obsessive—compulsive disorder, unpragmatic obsessions and extreme narcissism, Sheldon does not understand why humans are illogical and attempts to be logical himself. Even though, in reality, he is actually significantly more illogical than most people in so many ways i.

He possesses an eidetic memory and an IQ of , although he claims his IQ cannot be accurately measured by normal tests further ascertaining his egotism Sheldon has a generally excessively extensive knowledge of most philosophical principles of certain topics of interest, such as shown by his comments regarding various details of anecdotal knowledge for instance, about the introduction of the fork into Thailand.

Sheldon Cooper

He told Raj that he automatically sees prime numbers as red and that twin primes appear pink and smell like gasoline. These are characteristics of people with synesthesia. Sheldon also has qualities associated with being a prodigy, such as an inflated ego, social ineptitude, and an inability to relate emotionally with other people.

Despite his intelligence, he has a distinct lack of emotional maturity and is often baffled by even the most common social interactions. He not only fails to understand the simplest sarcastic jokes made by his friends, but also regards their sadness over problems with blatant confusion.

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Recently, he has begun to understand the concept of sarcasm, attempting unsuccessfully to employ it himself towards Penny in the second season, and successfully employing it towards his other friends in the third season. He appears to have a complete disinterest in romantic relationships, and his eccentricities, direct remarks, and demanding nature put him at odds with his own friends and especially Penny. Up until " The Empathy Optimization ", Sheldon never seemed to have any sense of remorse or guilt.

Perfect examples of this include when he ratted out Leonard, Raj, and Howard for sexual behaviour to Human Resources just because he thought he did nothing wrong, and when he puts down Amy by not treating her accomplishments like they were a big deal. Sheldon is extremely arrogant, narcissistic, selfish and utterly self-righteous. According to Sheldon's Meemaw, it's strongly implied that Sheldon takes after his grandfather, Pop-pop, who was known for being "a stubborn, egotistical man". When the group find an actual prop of the One Ring from Lord of the Rings Sheldon immediately snatches it off Howard, bluntly declaring ' Mine!

When he does not get the ring, he constantly tries to retrieve it, to the point of invading his own friends' privacy and boundaries and effectively stealing it off them e. This particular example shows that his great love for a fictional movie or rights cause him to be extremely obsessed with things that don't really matter in the context of the real world. In conclusion, it can be axiomatically ascertained that Sheldon will try to achieve, retrieve or maintain anything if it meant that he would seem fictionally or genuinely superior to everybody else.

Sheldon adheres to the roommate agreement constantly when things do not go his way and, interestingly, Sheldon has styled the roommate agreement so that everything goes his way. Also, Sheldon officiates in said agreement that he settles all ties, increasing the likelihood that he gets what he wants. That being said, when a clause of the Roommate Agreement applies to him to not do something, he will treat it like it is ridiculous - in the process, hypocritically violating the Agreement despite constantly chiding Leonard when he apparently violates it.

He also, at one point, when Leonard headed a project for the group, Sheldon labelled him as simply the founder, whilst he was chief or head of absolutely everything else, making him in charge. He also tried to make the project named after himself, even trying to get by naming the project with his name spelt backwards. Sheldon is revealed by Priya to have repeatedly violated the roommate agreement, and the several demonstrations of this cause deep discomfort and even despair in Sheldon, who becomes vengeful and deliberately damages Leonard and Priya's relationship through blackmail afterwards.

Sheldon does not see fault in absolutely anything he does in his life, to such an extent that he doesn't think that, when he commits a serious crime, he is doing anything wrong. He, at one point, insulted a judge whilst in court, simply because of his belief that his job and status was superior to the judge's, which landed him in prison in the first place.

Sheldon also stalked President Siebert just to get a simple answer out of him, to the point of following him to his home and then calling him anonymously. Sheldon is willing to steal to get what he wants, and bully anybody to do so as well. A prime example is when he deliberately puts all of Penny's clothes on a telephone wire without acknowledging, or even probably noticing, that this was outright bullying of somebody without any moral reasons other than self-righteousness and phenomenal delusions of authority on his part.

He sees it as his absolute right to interfere with something that does not involve him, and alter it so that it benefits or pleases him, shown at one point when he interfered with Leonard's dating another woman despite it not concerning him at all. Another example is when Penny, after an argument with Leonard which upsets Sheldon, says that "this really isn't about you" his only strained response - after a very long pause - is "I don't follow", showing that he doesn't understand why he cannot be priority one in situations that don't even involve him.

Sheldon also does not realize at all that he is an immense burden to everyone around him due to his controlling, condescending and demoralizing behaviour - he rather sees himself as a true privilege to his friends simply out of egomania. Sheldon is openly pompous and condescending towards people like Howard, treating him like a simpleton - to say the least - constantly.

His incredible sense of pomposity is so widespread that he immediately places himself in a position of absolute power, credit, benefit or authority in whatever project, ambition or situation which is discussed within earshot of him. He will also meet every single opposition to his authority with immense melodrama - he describes Leonard's control of one notable project as 'Leonard's reign of tyranny', despite being a dictator himself. He is also completely taken off guard when he is excluded from the project, because he is absolutely incapable of seeing anything he has done as a bad thing.

He does not do an approximately minuscule amount of personal labour if he could avoid it, shown by how he is seen with Howard and Raj both carrying huge workloads of Christmas presents, whilst he is only carrying a small cylindrical present in one hand and eating ice cream with the other. He appears completely indifferent, if not apathetic to the fact that they are on the edge of collapsing from exhaustion and could be crushed under the weight. Another supreme example is when he realizes that Amy is going to work at the same university as he is, and he simply goes over to her house and says ' You can't work where I work ', thinking that he has complete jurisdiction over where she works.

Another key example of Sheldon's selfishness is when he is ill. Sheldon demands that everyone else take care of him, even if they are occupied with other tasks or could be hurt or ill themselves due to never having been ill alone before. He also believes that being ill entitles him to be rude to others as shown during The Empathy Optimization, Sheldon was completely ungrateful and insulting to his friends and did not realize this until Leonard made him remember. Although it is not confirmed, Sheldon appears to have extreme megalomaniacal tendencies - when he was a child, the kind of pet he wanted would be one that was capable of killing at telepathic command.

He also, at several points in his childhood, tried to build devices and technologies that would enable him to kill or avenge himself on people who had done him wrong. At several points in his life, he fantasizes about "rising to power", gaining a planet that he can rule with an iron fist, even declaring that he will, one day, have a robot army at his disposal. In addition to this, Sheldon constantly brags that he will, one day, gain a Nobel Prize and suggests to several people that their contributions to his life will earn them a mention in his memoirs A mention reading "You're welcome, mankind".

He also sees himself as a world-renowned physicist with an unparalleled understanding of the universe and that he is on the precipice of advancing mankind's understanding of the universe, ignoring the fact that there are some aspects of even science that he has some lack of understanding of, and he is notoriously able to make scientific mistakes - he was rendered absolutely speechless by an equation in a physics bowl which he didn't know the answer to, and was so angry that he couldn't figure it out that he denied the correct answer when it is provided.

What this means generally is that he believes that mankind owes him big time, and has done so his entire life. Sheldon's opinion of his own profession is overly heavily ego-oriented, to the point where if he sees any occupation of someone else's that is unrelated to his, he tacitly and implicitly admonishes them and boasts about his own.

This is exemplified by his extremely low opinions of Howard's profession as an engineer he constantly scorns Howard's intellect based on him not having a Ph. D and the fact that he is an engineer , his surmisations that geology is "the Kardashians of science" and his discredited opinions of biology as a low point on the scientific ladder simply on the basis that it is, in his own words, "all about yucky, squishy things".

However, despite scorning engineering as unimportant, he is shown to be somewhat extremely knowledgeable in the subject himself in terms of general knowledge certainly not field work , and therefore only condescends the subject because he finds the information and premise inferior to that of physics. Sheldon has remarked that it is his dream to be an astronaut, and that he was secretly stunned at Howard being chosen to go into space, stating in his own words that it showed him "they'd just send 'anyone' up there".

Sheldon's expression of his more advanced intelligence has gotten him fired from his job, and even Leonard is surprised to learn that Sheldon is conceited enough to believe that Isaac Newton is intellectually inferior to himself. Sheldon hates it when someone stops him when he is trying to explain something.

If he is, a violent tic starts on his face until he can complete what he wants to say, as in The Friendship Algorithm when he is prevented from explaining why tapioca pudding is a jiggling bowl of potential death. He cannot and will not drive, and thus someone must always drive him unless in an extreme circumstance like when he drives Penny to the emergency room in " The Adhesive Duck Deficiency ". He also shows symptoms of obsessive compulsive personality disorder and Asperger syndrome , e. He refuses to sit anywhere other than his designated spot on the couch and follow set routines, and the running gag of the show is that when he knocks on Penny's door, he has to say Penny's name every three knocks he does this thrice every time.

The series creators do not want to specifically identify Sheldon's specific psychological malady. Sheldon occasionally uses slang in a very unnatural fashion , and follows jokes with his catchphrase " Bazinga! Despite his ego-centrism, Sheldon appears to be somewhat aware of his social ineptitude, particularly his lack of understanding of sarcasm. He mentioned that he keeps a record of his daily conversations after Penny snapped at him and Leonard asked him why, to which he suggested that Leonard check his conversation records "to see if I messed up anywhere.

In " The Toast Derivation ", Sheldon was revealed to have criticized Bill Gates for focusing on his charity work rather than Windows Vista, a remark that earned him a punch in the face. Sheldon also possesses some understanding of other religions such as Hinduism and corrects Rajesh when he says cows are gods, when they are actually like gods and was also knowledgeable about other Hindu beliefs however despite being raised in an extremely religious household, Sheldon possesses no faith in Christianity and even after moving back to Texas and planned to teach the religious types evolution and only moving back when his mother calls evolution opinion.

Sheldon dons karma as "nonsense" and was left baffled when Rajesh compared it to Newtonian. Sheldon is extremely germaphobic and is very extreme in his methods to avoid catching an illness such as sterilizing his mouth with whiskey after sipping from Leonard's glass. Sheldon does his best to avoid any human contact however as the series continues he became more, if not a very slightly affectionate person such as hugging Leonard after he returned from Professor Proton's funeral and kissing Amy on board a locomotive.

Sheldon does show on rare occasion interest in relationships, which was most prominently seen with Amy Farrah Fowler ; however, he does not express it directly, instead of developing strange behavior patterns such as buying cats or refusing to open discussion to the matter. Despite this however, Sheldon remains completely clueless to sexual innuendos which were present during his and Amy's anniversary and she became intoxicated which causes her to unbutton her blouse and asks that they skip to dessert for Sheldon to reply "I just had clobber.

When Rajesh, Leonard, Wolowitz and Sheldon were competing over The One Ring and Penny appears with "a bag from Victoria's Secret", Sheldon and the rest all look at Leonard, he either understood what Penny meant or was looking because everyone else was. Because of his eccentric and arrogant behavior, Sheldon is not well-liked by many people.

Due to his belief that he is intellectually "superior", he's not ashamed to insult his own friends, like Leonard , whose work Sheldon deems derivative and who never appreciated his overbearing mother ; Howard, who is merely an engineer and not a real scientist, and also does not possess a doctorate despite the fact that engineering has more practical real-world applications, as well as more related jobs, than theoretical physics does, a fact that Sheldon does not take into account ; and Penny, who Sheldon considers and in some ways, is the polar opposite of an intellectual.

He often mocks her for having once dropped out of a community college. In " The Thespian Catalyst ", Sheldon makes a speech to a class of bored and disinterested grad students, reminding them that they will never be as smart as he is. Sheldon's obsession with routine constantly causes friction with him and his friends. In " The Dumpling Paradox ", he has an issue with Penny sleeping on the couch, because he wants to watch Doctor Who and Penny is sleeping in his spot.

Leonard offers some alternatives, but Sheldon refuses to accept them, because they're not part of his routine. In the same episode, he states that he, Leonard and Raj can't order Chinese food without Howard. Sheldon's routine is even written for everyone to view except for to in the afternoons, where he spends some recreational time in a storage room in the Caltech basement. Even his recreational time is planned and he spends it doing the same thing -- playing keepie uppie with a hacky sack. Sheldon has also been shown to have issues with closure, having a near meltdown when he learned that one of his favorite sci-fi shows, Alphas , had been cancelled after a cliffhanger.

Also, due to his lack of emotion and his inability to understand sarcasm, Sheldon never seems to realize when he's in trouble. When other people get mad at him, he blames them their inability to "properly" understand the situation or the fact that they can't control their emotions. In " The Einstein Approximation ", Sheldon tries to get a menial job. The woman at the employment office doesn't understand his behavior, and when he tells her he works as a physicist at Caltech, she thinks he's crazy and calls security.

Sheldon isn't fazed by this, because in his mind, he's done nothing wrong, and he casually waits for her to return so they can finish. Sheldon has also been shown to be very impatient. This would come back to haunt him as he would hound Amy after she told him she needed space. Unable to understand this, he showed up after 11 hours, thinking that that had been enough time. He also continuously asked Amy whether they had actually broken up or not without giving her time to think about it.

He ultimately went too far, causing her to officially break up with him. Sheldon also possesses many child-like qualities. For example, even though he is unaware of it, Sheldon is extremely stubborn. He cannot stand to be interrupted, concede when he doesn't know something, or hear people bicker or argue, crinkling his lips with intense frustration when any of these events occur.

Sheldon has not attempted to obtain a driver's license although he does possess a learner's permit , and needs his friends to drive him everywhere; he refuses to take the bus. He attempts to learn to drive on a simulator. However, he fails instantly. Sheldon's excuse for this is that he is "too evolved" to perform "plebeian tasks" such as driving. Leonard asked why she did not ask Sheldon to go instead. Amy answered that Sheldon behaved like a child the last time so he is out.

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After Amy left, Sheldon said in a sing-song tone to Leonard; "Ha-ha, you have to go to a wedding! He has also shown some slightly childish fear. In the Season 2 Episode, " The Euclid Alternative ", Sheldon mutters something that shows that he has a night-light "Maybe I could keep my sheets if I turn out the night-light".

Like his friends, he is scientifically inclined, and is fond of comic books, costumes, video games, flags and science fiction, specifically Battlestar Galatica , Doctor Who , Stargate series, Star Trek , Star Wars , and Firefly , although he strongly dislikes Babylon 5 because he thinks it lacks scientific integrity and is derivative.

He has claimed to be an honorary graduate of Starfleet Academy , and is an avid fan of science officer Spock. He likes playing Halo every Wednesday and paintball on the weekend with his friends. He can also play the piano and theremin , and seems to be a very good Tuvan throat singer , but would be better if not for a part in the Roommate Agreement denying him practice.

Sheldon is a tall, lean, yet well-built man, originally in his late twenties, but he's in his late thirties by now. His wardrobe consists of vintage T-shirts which he always wears over a long-sleeve adorned with references to superheroes, quantum physics, Sci-Fi television shows, and robots.

Sheldon often expresses his mood through his choice of attire; especially his t-shirts. He's got a collection SO large in fact, that it has its own page on the Wiki under Sheldon's Wardrobe. He also owns a dark blue plaid suit which he wears for lecturing and other formal occasions. He also appears to enjoy Reddit , as he has been seen with a Reddit alien shirt. He usually wears a long sleeve shirt underneath it along with plaid pants. Sheldon is tall and thin setting him apart from his shorter colleagues , with Penny, and later Leonard, saying he looks like a giant praying mantis.

In Season 1 of Young Sheldon , Sheldon is a rather tall, skinny, adorable 9 year old kid 10 later on. He is about 4' 5" 1. In fact, in The Big Bang Theory , while he is an adult, his fashion is more kid-like, however, in Young Sheldon , while he is a kid, his fashion is more adult-like. With few exceptions, Sheldon refuses all drugs, including alcohol and caffeine, as a promise to his mother though it's suggested in " The Codpiece Topology " that he drinks Red Bull, which contains caffeine.

In addition, when Penny mixed alcohol into his drink making it "slutty", he began to play the piano and sing "To Life" from the musical Fiddler on the Roof in front of an audience. A small amount of coffee made him extremely hyperactive, but unproductive in another episode. Taking Valium also affected his behavior. Probably the most infamous time of him being drunk was when he had to give a speech in " The Pants Alternative " and he acted like a comedian due to the abundance of wine he drank to calm his nerves.

The scene was uploaded on YouTube where it is revealed Sheldon also took off his pants and mooned the audience. Howard once drugged him with his mother's sleep medication to get him to stop talking, but was unsuccessful. While it is argued that Sheldon drank beer in the " Pilot ", it is actually an orange soda clearly seen when Leonard holds up his bottle in the hallway. He does enjoy a Mountain Dew in " The Vengeance Formulation ", one of the more caffeinated sodas, even calling it "refreshing". He also likes "diet virgin Cuba Libres ", which is essentially a Diet Coke with a slice of lime.

It appears that he can drink caffeinated beverages to a certain point, but not to the extent of coffee which he considers a drug. In " The Habitation Configuration " Penny serves him numerous glasses of Long Island Iced Tea which he enjoys -- however, he is unaware of the fact it is alcoholic and not actually tea as he genuinely believes and Penny makes no move to correct his assumption. This drastically affects his behavior to the point where he attempts to 'beat' an apology out of Wil Wheaton. In " The Thanksgiving Decoupling " he drinks beer with Bernadette's father since his own father died before they could do so.

As a result, he became drunk and did numerous things, like burping pi, or as much as he could without throwing up, making fun of Howard's mother and her "bathroom clowns" by saying you could only fit one of her in a car, and insulting Howard, calling him the "clown that came out of her". After apologizing for his behavior, he sent Amy to get him and Mike beers and slapped her on the butt, much to her pleasure. Later, he threw up on the clowns in the bathroom. Despite his strange behavior, Sheldon had, at times, demonstrated a much softer side to himself. He does seem to be a quite heartwarming character; however, these moments are rather rare, and usually only reserved for those closest to him, such as his mother, Meemaw, Amy and his friends.

Although his friendship with Leonard is usually strained because of Sheldon's quirky behavior and weird habits, Sheldon has called Leonard "his little buddy" or something of the sort on multiple occasions. He also shows an obvious unease whenever his friendship with Leonard is threatened. Sheldon has also showed friendly acts of caring towards Penny. In one instance, when Penny was low on money, Sheldon let her borrow a large amount of his savings, but while she worried about paying it back, he was entirely unconcerned as to when he got it back.

Sheldon's willingness to lend money to others was later described by Leonard as "one of the few idiosyncrasies that doesn't make you want to, you know, kill him". Also, after Penny let him stay at her place when he locked himself out of his apartment, Sheldon sincerely thanked her for it. When Penny fell and dislocated her shoulder, Sheldon spent the entire night taking care of her, including driving her to the hospital despite the fact that he does not know how to drive. He finished the night by helping her into bed and singing " Soft Kitty " to her after she asked him to.

He also hugged Penny again when she said she would talk to Leonard about having him take Sheldon to Switzerland rather than her. This prompted him to sincerely thank her and hug her. When Howard's mother died, Howard fell into a depression as Sheldon told him he understood his pain as he lost his own father and though he didn't have friends at the time to help, Howard did causing the latter to smile as these comforting words.

This was one of Sheldon's kindest moments as all his friends expected him to be rude especially Leonard and Penny who were moved by his words. With Amy, he specifically cuddled with her in the episode "The Isolation Permutation", after a discussion to console a weepy Amy who was craving human intimacy and physical contact. After turning down Amy's previous proposals of getting into bed together and French-kissing, Sheldon agreed with her final offer to cuddle, though he got upset over it later, by yelling at Leonard and Howard to keep Penny and Bernadette in line and have them apologize to Amy since consoling Amy had caused him to miss the time he had designated to solve Space-time Geometry in Higher Spin Gravity and building his Lego Death Star.

This particular event of him cuddling with Amy is a huge development of his personality since he is not shown to have much empathy or sympathy for others. His caring attitude towards Amy is also exemplified when he buys her a diamond tiara as a form of apology after having a fight regarding the importance of Amy's accomplishment when her research made the cover of a noteworthy science magazine. In another instance, Sheldon acted disrespectfully in Amy's laboratory when he was taking his required vacation time.

The next day, however, he returns and after a few attempts, meekly apologizes to Amy, showing a vulnerable side of him that isn't usually seen considering his egotistical attitude. Perhaps the greatest leap forward in Sheldon's willingness to show his softer, more emotional side to Amy is when he voluntarily, without any prior prompt from Amy, held Amy's hand while Howard's Soyuz capsule was being launched into space.

Amy was shocked at this, since Sheldon had acted confused and oblivious when she had tried holding his hand in The Alien Parasite Hypothesis. In season 6, he objects to Amy making him hold hands as he considers it unhygienic. After 8 seasons, he finally enjoy making out with Amy after being disturbed by it.

Following Amy's birthday, he decided to have coitus with her in season 9 to show her how much he cared fore her. He later admitted that he gets turned on by interaction with her in season Shamy seems to get turned on discussing or arguing about science. Along time ago, he always been rude and offends a lot of people. Mostly he never apologizes for being a jerk.

In later seasons, he started maturing and starts apologizing to people every time he is being a jerk or being rude. When somebody tells him. In the series finale, he was going to make a speech about his narcissistic personality when he won the nobel prize and rub it in people's face.

He thanked his friends and his family for making him a better person and help his get him up all the way up to the nobel prize. In contrast to his profoundly religious mother and devout Christian upbringing, Sheldon has no interest in religion - he tends to ignore or express dislike for religious celebrations such as Christmas, and wastes no time in bringing up the Pagan origins to each festival. Additionally, his scientific beliefs often come into conflict with the spiritual beliefs of his mother, Mary. Nevertheless, he has an agreement with his mother to attend church once a year, and once exclaims "Thank you, Jesus!

His attitude towards God has been hinted at being of an Agnostic nature, when in the episode The Zarnecki Incursion he says "Why hast thou forsaken me deity whose existence I doubt When he sees his mother having sex, he is very concerned about the hypocrisy shown by his mother having relations outside of marriage yet expounding the Bible to him throughout his childhood, even going as far to declare "don't turn to him, he's mad with you" when his mother uttered "oh dear Lord" during the conversation.

He possesses knowledge of other faiths, such as Hinduism. Sheldon also appears to have problems understanding the law at times. Sometimes, his expertise of lock-picking gets him in trouble. He is shown to drop objects out his window into traffic without any regard, in addition to breaking into buildings. He has also been seen going into various places, such as a kid's play-area, and even began working at the Cheesecake Factory without being granted permission.

He has expertise with picking locks and disarming alarm systems. Furthermore, the Department of Homeland Security notifies his mother when he acts contrary to federal law. As he states later, "Apparently, you can't hack into a top-secret government supercomputer and then try to buy uranium without the Department of Homeland Security tattling to your mother. He also states that he has been arrested for jaywalking when he said to a police officer 'You just saw me jaywalk, aren't you going to arrest me. Maybe I should arrest you for impersonating a police officer'.

Another notable trouble with the law involves Sheldon going to court for running a red light when taking Penny to the emergency room. This resulted in Sheldon being found guilty and forced to pay the cashier, only for him to insult the judge and being thrown in jail simply because he refused to apologize for his comments. In addition to apologizing to the traffic court judge and paying the fine, Sheldon was forced to accept three points on his non-existent driver's license. Though Sheldon has never been confirmed as having Asperger's syndrome, many of his traits and much of his behavior exemplify it.

These qualities include social ineptitude and many more traits which make him the most eccentric and bizarre of the characters in the show. Many of these traits are the reasons why Leonard finds him hard to live with and his friends find him so hard to be around. These include:. He also keeps a record of what he considers faux pas "strikes", which he allocates to those who violate his self-imposed conditions. Upon receiving three strikes, Sheldon gives them the choice of apologizing, being "banished" from the apartment for a year, or taking a "class". My mother had me tested. Despite Sheldon's personality disorders and difficult habits, his friends usually just do what he says because it is easier.

It has also been revealed that Sheldon has a bifurcated uvula, something which he is self-conscious about. The most notable feature of Sheldon's obsessive-compulsive disorder is his refusal to sit anywhere other than his designated spot on the far left cushion of the couch in his apartment, which he considers his "single point of consistency in an ever-changing world" and "the singular location in space around which revolves my entire universe ", exceeding his love for his mother.

He describes his spot on the couch as being his point 0, 0, 0, 0 if his life were a Cartesian coordinate plan. Sheldon regularly reproaches Penny and other people for sitting in his spot. Even disruptions to this location are enough to disturb him. Although he did allow Penny to sit in his spot in the first episode, as well as Howard, for a short time in " The Apology Insufficiency ", only 94 seconds later, he reclaims his spot.

As well as his designated spot in the apartment, if Sheldon is ever in a different area where he is going to sit down, such as Penny's apartment , he has to choose the best sitting location based on such things as optimal television viewing, lighting, airflow, and cushion density. In "The Werewolf Transformation", when his barber was ill and chaos ruled his life, he didn't object to Penny sitting in his spot. In " The Mommy Observation " Leonard reveals that Sheldon has a very sensitive butt and can tell when someone was sitting in his spot.

Sheldon is the best friend of Leonard, as they live together and are accustomed to tolerating each other's quirks ever since Sheldon put out an ad for a roommate with a list of criteria to follow. When Leonard first met Sheldon he had a bunch of rules that Leonard had to follow. Despite Sheldon sometimes making remarks to the contrary, he appreciates Leonard and assures Leonard that his friend will not die alone.

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Sutherland, Nadia R. Azar, and Sean Horton. Evaluating posters advertising sexual assault education on campus , Charlene Y. Evaluating risk effects of industrial features on woodland caribou habitat selection in west central Alberta using agent-based modelling , Christina A. Semeniuk, M. Musiani, M. Hebblewhite, S. Grindal, and D. Evaluation of alternative approach for suspension corner damping by the use of hydraulic top mounts , Salvatore Marco Cubisino.

Evaluation of the anti-cancer activity of a curcumin analogue alone and in combination with current chemotherapeutics , Krishan Parashar. Everything Begins as a Memory , Tim Fogarty. Kelly, Charles H. Fransen, Daniel D. Heath, and G. Douglas Haffner. Evidence of sound production by spawning lake trout Salvelinus namaycush in lakes Huron and Champlain , Nicholas S. Johnson, Dennis M. Higgs, Thomas R.

Binder, Ellen J. Marsden, Tyler J. Buchinger, Steven Farha, and Charles C. Grebe, Joshua Jaekel, and Jalal Ahamed. Exploring seascape genetics and kinship in the reef sponge Stylissa carteri in the Red Sea , E. Giles, P. Saenz-Agudelo, N. Hussey, T. Ravasi, and M. Female song in the hooded warbler , Lesley J. Evans Ogden, Diane L. Neudorf, Trevo E. Pitcher, and Bridget J. Hussell, David Lamble, and Oliver Love. Food web structure in oil sands reclaimed wetlands , K. Kovalenko, Jan J. Ciborowski, C. Daly, D. Dixon, A.

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Farwell, A. Foote, K. Frederick, J. Costa, K. Kennedy, K. Liber, and M. Forecasting the outcome of multiple effects of climate change on northern common eiders , Cody J. Dey, Christina A. Semeniuk, Samuel A. Front Matter , Jonathan Mertz. Kovalenko, Valerie J. Brady, Jan J. Ciborowski, Sergey Ilyushkin, and Lucinda B. Further analysis supports the conclusion that the songs of Screaming Pihas are individually distinctive and bear a lek signature , Lauren P.

Fitzsimmons, Nicole K. Barker, and Daniel J. Fuzzy cognitive mapping as a tool to define management objectives for complex ecosystems , Benjamin F. Hobbs, Stuart A. Ludsin, Roger L. Knight, Phil A. Ryan, Johann Biberhofer, and Jan J. Gala Dinner and Motown Dance. Gender Brechting , Patrick Moriarty. Genetic architecture and maternal contributions of early-life survival in lake trout Salvelinus namaycush , Aimee Lee S. Houde, C. Genetic architecture of gene transcription in two Atlantic salmon Salmo salar populations , X. He, Aimee Lee S. Houde, Trevor E.

Pitcher, and Daniel D. Perepelizin, Elizabeta Briski, Melania E. Cristescu, and Hugh J. Geochemistry and geochronology of mylonitic metasedimentary rocks associated with the Proterozoic Miaowan Ophiolite Complex, Yangtze craton, China: Implications for geodynamic events , Ali Polat. Healthy heart, happy life: resources about chronic heart failure , Samantha Brown and Mia Zecca.

Higher colonization pressure increases the risk of sustaining invasion by invasive non-indigenous species , Hugh J. MacIssaac and Mattias L. Hockey and the Black Experience , Bob Dawson. How do Canadian racialized sport media personalities influence conversations within digital spaces? Razack Ms. How is shame resolved? An experimental study on the roles of anger and sadness , Tsubasa Sawashima.

How To See Detroit? Muhly, Christina A. Human-mediated and natural dispersal of an invasive fish in the eastern Great Lakes , Mattias L. Johansson, Bradley A. Dufour, Kyle W. Wellband, Lynda D. Corkum, Hugh J. MacIsaac, and Daniel D. Human speedy: A novel cell cycle regulator that enhances proliferation through activation of Cdk2 , Lisa A. Porter, R. Dellinger, J. Tynan, E. Barnes, M. Kong, J. Lenormand, and D. IL correlates with the expression of carboxypeptidase B2 and lymphovascular invasion in inflammatory breast cancer: The potential role of tumor infiltrated macrophages , Hossam T.

El-Ghonaimy, Sherif A. Ibrahim, Zainab A. Importance of behaviour to the re-establishment of drifting Ephemeroptera , Jan Ciborowski and Lynda D. Inconsistent geographic variation in the calls and duets of Barred Owls Strix varia across an area of genetic introgression , Karan J. Indigenous Opening and Welcome , Theresa Sims. Individual variation and lek-based vocal distinctiveness in songs of the screaming piha Lipaugus Vociferans , A suboscine songbird , Lauren P.

Maclsaac, W. Gary Sprules, and J. Intensive sampling and comparison of methods in detection of non-indigenous species , Sharon Lavigne. Interplanar coupling-dependent magnetoresistivity in high-purity layered metals , N. Kikugawa; P. Goswami; Kiswandhi, A. Kiswandhi, A. Choi; D. Graf; R. Baumbach; J. Brooks; K. Sugii; Y. Iida; M. Nishio; S. Uji; T. Terashima; P. Rourke; N. Hussey; H. Takatsu; S. Yonezawa; Y. Maeno; and L. Introduction , Katherine Quinsey.

Angel, Melania E. Invasion risk of active and diapausing invertebrates from residual ballast in ships entering Chesapeake Bay , Ian C. Duggan, Sarah A. Bailey, Colin D. Blackburn, James T. Carlton, Jamie T. Dick, Philip E. Hulme, Josephine C. Iacarella, Jonathan M. Jeschke, Andrew M. Liebhold, Julie L. Lockwood, Hugh J. Richardson, Gregory M. Ruiz, Daniel Simberloff, William J. Sutherland, David A. Wardle, and David C. Carlton, Jaimie T. Investigating effects of behavioural flexibility and neuroplasticity on acclimation success of outcrossed Chinook salmon Oncorhynchus tshawytscha : applications in aquaculture , Jessica Lauren Mayrand.

Doucet, Matthew D. Shawkey, Geoffrey E. Hill, and Robert Montgomerie. Andrews, Kevin J. Milne, and Cheri L. Is There a Gay Brain? Joint analysis of stressors and ecosystem services to enhance restoration effectiveness , J. Allan, P. McIntyre, S. Smith, B. Halpern, G. Boyer, A. Buchsbaum, G. Burton, L. Campbell, W. Chadderton, Jan J. Ciborowski, P. Doran, T.

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Eder, D. Infante, L. Johnson, C. Joseph, A. Marino, A. Prusevich, Jennifer G. Read, Joan B. Rose, Edward S. Rutherford, Scott P. Sowa, and Alan D. Jules Robinet "Mr. Keynote: Animal abuse and interpersonal violence: The evolution of a research domain , Frank Ascione. Keynote Presentation - Reducing sexual violence: From pilot research to international scale-up in 15 years , Charlene Senn.

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Yurkowski, Steve Ferguson, Emily S. Choy, Lisa L. Loseto, Tanya. Brown, Derek C. Muir, Christina A. Semeniuk, and Aaron T. Let's Get Fuzzified , Hannah Burdett. Gewurtz, Nilima Gandhi, Ken G. Liberation theology as a transnational social movement: the case of the North American sanctuary movement , Shawn Micallef. Liquid Crystalline Tetraazaporphyrins , Rahul Jayachandiran. Patel and Huiming Zhang.

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Memoir of discovery (Autism and the Inferior Colliculus Book 3) Memoir of discovery (Autism and the Inferior Colliculus Book 3)
Memoir of discovery (Autism and the Inferior Colliculus Book 3) Memoir of discovery (Autism and the Inferior Colliculus Book 3)
Memoir of discovery (Autism and the Inferior Colliculus Book 3) Memoir of discovery (Autism and the Inferior Colliculus Book 3)
Memoir of discovery (Autism and the Inferior Colliculus Book 3) Memoir of discovery (Autism and the Inferior Colliculus Book 3)
Memoir of discovery (Autism and the Inferior Colliculus Book 3) Memoir of discovery (Autism and the Inferior Colliculus Book 3)

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