Synergistic effects of

cytokines on β-AP-induced microgli

Synergistic effects of

cytokines on β-AP-induced microglial neurotoxicity One reason for conflicting results may be that prior studies of β-AP-induced microglial neurotoxicity largely ignored important costimulatory agents present in the AD brain. The extracellular environment surrounding neuritic plaques in the AD brain is rich in a variety of proinflammatory agents including cytokines,6 which are likely to augment the effects of β-AP on microglia. It has been reported that interferon-γ, phorbol ester, and lipopolysaccharide (LPS) all augment the effects of β-AP on Bosutinib cost microglia and monocytic cells.27,38,46 However, none of these augmenting stimuli have a physiologic Inhibitors,research,lifescience,medical role in AD. Our group has focused on two cytokines known to be increased in the central nervous system (CNS) in AD, macrophage colony-stimulating factor (M-CSF) and interleukin-1 (IL-1), both of which are microglial activators. M-CSF (produced by neurons, astrocytes, and endothelial cells)47-52 induces proliferation, migration, and activation Inhibitors,research,lifescience,medical of microglia.53-56 After traumatic brain injury, microglial expression of the M-CSF receptor (c-fms) is greatly increased.57 M-CSF treatment of microglia induces increased expression of macrophage scavenger receptors (MSRs).52 Microglial adhesion to β-AP, internalization Inhibitors,research,lifescience,medical of β-AP, and possibly β-AP-induced microglial activation may be

mediated by MSR class A.58,59 β-AP also interacts with neuronal receptors for advanced glycation end products (RAGEs) to increase neuronal MCSF expression,52 which causes further microglial activation. Neuropathologic studies show increased immunoreactivity for the

M-CSF receptor (c-fms) on microglia in AD brain,60 and Inhibitors,research,lifescience,medical M-CSF-labeled neurons colocalize with β-AP deposits. M-CSF levels in AD cerebrospinal fluid are five times greater than in controls.52 We found that cerebrospinal fluid tau, a marker for neurodegeneration in AD, is positively Inhibitors,research,lifescience,medical correlated with cerebrospinal fluid M-CSF in AD (Figure 1). This may indicate that higher CNS M-CSF levels are related to neurodegeneration. Granulocyte-macrophage colonystimulating factor (GM-CSF), another astrocyte product, also induces proliferation of microglia.54 However, GMCSF does not have effects identical to those of M-CSF. For example, GM-CSF can paradoxically induce ramification of cultured microglia, whereas M-CSF SB-3CT does not.61 The proinflammatory cytokine IL-1 is thought to play a key role in neuronal injury in AD. IL-1 is increased in the brain in AD,62 and is associated mainly with activated, phagocytic microglia near plaques.63 IL-1 immunoreactive microglia are found near diffuse as well as neuritic plaques, suggesting that IL-1 is important in the early stages of plaque formation.64 IL-1 affects expression and processing of beta-amyloid precursor protein.65-66 In the AD brain, the regional distribution of IL-1 immunoreactivity strongly parallels β-AP deposition.

0, Sony Pictures Digital Inc , TX) All three types of stimuli la

0, Sony Pictures Digital Inc., TX). All three types of stimuli lasted 130 msec. The “Standard” stimulus was a sound with frequencies increasing linearly from 250 to 1000 Hz, while the “Target” stimulus was a sound with frequencies decreasing linearly from 1000 to 250 Hz. “Novel”

stimuli consisted of different 130 msec noises (e.g., onomatopoeia sound effects used in cartoons). Interstimulus intervals lasted 800 msec during which subjects Inhibitors,research,lifescience,medical could hear in background the scanner noise. All stimuli were presented during a silent gap and baseline recorded in silent gaps without stimulus presentation. Participants were instructed to respond as quickly as possible with their right thumb (pushing a button) at the occurrence/recognition of every “Target” stimulus. The task thus demanded strong attention associated with a muscular reflex. During auditory Inhibitors,research,lifescience,medical stimulus presentation, subjects were instructed to watch a gray screen with a fixation point (black cross). Presentation®

software ( was used to present stimuli, to register the subject’s responses and to analyze the behavioral tests Inhibitors,research,lifescience,medical (i.e., reaction times, intrasubject reaction times variability, error rates). Before the actual start of the scans, subjects were trained outside the scanner in order to familiarize to stimuli and handling of the system. All subjects were able to perceive sounds and operate the response keys correctly. By contrast, tinnitus could not be perceived because masked by the experimental environment. In order to ensure comfortable hearing of stimuli in the noisy MRI environment, we performed some acoustic measures inside the scanner before optimizing the setup for the transmission of the auditory stimuli. The mean acoustic sound pressure Inhibitors,research,lifescience,medical level (SPL) during fMRI scans was 80 dB

SPL with a very narrow spectral peak of 120 dB SPL at 1.12 kHz. To reduce scanner noise, a passive sound-attenuating cylinder was inserted into the bore of the scanner. It was composed of two layers of 5-mm-thick sound-attenuating material (Plastison®, fixed on a rigid cylindrical support (Sonotube®, Inhibitors,research,lifescience,medical Furthermore to improve hearing of the stimuli, those imaging slices were acquired in three stacks. Acquisition of each stack took 800 msec. Stacks were separated by a silent gap of 130 msec (gradient system “off”), during which period the auditory stimuli were presented. Subjects wore earplugs and stimuli were transmitted by home-made prototype earphones inserted in industrial hearing protectors (Bilsom®). The frequency range of the stimuli (250–1000 Hz) was below the peak frequency of the echo-planar imaging (EPI) Paclitaxel cell line sequence. fMRI protocol Blood oxygen-level-dependent (BOLD) images were acquired on a 3-Tesla whole body MR scanner (Brucker Medspec S300, Ettlingen, Germany) using gradient-echo planar imaging (EPI). Images of the whole brain, including cerebellum and brainstem, were obtained.

3) The applicability of the 50 mM ammonium acetate buffer (pH 9 3

3) The applicability of the 50 mM ammonium acetate buffer (pH 9.3) in the preparation of AQC amino acid derivates for direct infusion experiments was evaluated. Derivatized amino acid standard solutions (1 × 10−2 g/L) were infused into the Xevo TQ mass spectrometer. Multiple reaction monitoring (MRM) transitions were determined for 26 amino acids, and the optimal cone voltage and collision energy associated Inhibitors,research,lifescience,medical with each transition were established (Table 1). Unlike previous

direct infusion experiments performed with the borate buffer, signal suppression and source contamination were not observed with this alternative buffer system, after 78 consecutive infusions. AQC amino acid derivatives were stable for more than three weeks when stored at room temperature in the dark, further advocating the effectiveness of this buffer for the derivatization reaction (data not shown). Table 1 MRM transitions, cone voltage (CV) and collision energy (CE) determined for AQC-derivatized standard amino acids

buffered Inhibitors,research,lifescience,medical with ammonium acetate (50 mM, pH 9.3). Experimental conditions: Waters XEVO TQ mass spectrometer; direct infusion at 20 µL/min; … The reproducibility of the derivatization method Inhibitors,research,lifescience,medical with the 50 mM ammonium acetate buffer (pH 9.3) was confirmed by the UPLC-ESI-MS/MS analysis. The peak area of the isotopically labeled amino acids derivatized with AQC in ammonium acetate medium was measured in Inhibitors,research,lifescience,medical nine replicates (final concentration of adducts = 4 × 10−4

g/L) (Table S1). As shown in Table S1, the relative standard deviation (RSD) of the peak area for all isotopically labeled amino acids was below 9%, indicating high reproducibility of the derivatization reaction. The Inhibitors,research,lifescience,medical efficiency of the reaction in the alternative buffer was further studied by evaluating the linearity of the detector response for standard amino acid solutions over the concentration range from 250 μM to 3.05 pM. Figure S1A and Figure S1B (supplementary this website information) show typical internal calibration curves of phenylalanine obtained by UPLC-ESI-MS/MS analysis under the conditions described in section 3.5. The response factors for these calibration curves were calculated using relative peak areas, in which the area of phenylalanine was divided whatever by the area of the internal standard, 4-hydroxyphenyl-2,6-d2-alanine-2-d1 (present at a constant concentration of 4 × 10−4 g/L after derivatization). Figure S1A displays the internal calibration curve for phenylalanine obtained with the conventional borate buffer, whereas Figure S1B shows the internal calibration curve obtained with the alternative 50 mM ammonium acetate buffer (pH 9.3). Clearly, both internal calibration curves exhibit similar response factors, correlation coefficients and slopes, providing additional evidence for the suitability of the ammonium acetate buffer for AQC derivatization of amino acids.

1 Hebb pointed at the tight connection between synchronization a

1 Hebb pointed at the tight connection between synchronization at the population level, representation, and learning. He suggested that the “… the simplest instance of a representative process (image or idea)” is a neuronal assembly, a group of “association-area cells” that share similar static and dynamic response properties when activated through specific receptors. Moreover, viewed from a perspective of purely mathematical principles derived from the machine learning and artificial intelligence realms, any agent that can learn complex Inhibitors,research,lifescience,medical tasks must develop some kind of internal representation of the outside world in which it resides. These and related conjectures from

the fields of psychology, engineering, and neurophysiology lead to the conclusion that the function of the nervous system, at the population or neuronal network level, can be studied in terms of three axes: representation, development, and learning. Representation denotes the study of how outside objects and sensations Inhibitors,research,lifescience,medical are “encoded” by neuronal Inhibitors,research,lifescience,medical activity and how these

activities interact to form higher-level complex functionality. Learning consists of the modification of these representations, their schemes, and the internal Selleck SB939 relations between them. The environment–development problem reduces to the following (rather vague) question: How does the richness of the environment experienced by a neural network during development affect its mature structure, topology, and functional capacities? In what follows we describe the use of multi-site interaction with large cortical networks developing ex vivo, in a culture dish, to study basic biophysical aspects of Inhibitors,research,lifescience,medical synchronization,

adaptation, learning, and representation Inhibitors,research,lifescience,medical in neuronal assemblies. We will briefly describe the experimental system, basic results regarding the self-organization of activity in this system, and the dynamical properties of neurons and networks in response to external stimulation. We show that the individual neurons and networks display very complex, history-dependent response patterns that pose constraints on possible representation schemes. Moreover, we will show the feasibility Thymidine kinase of such representation schemes and implications of their usage. Finally we will pose some future questions and research directions. THE EXPERIMENTAL SYSTEM: THE NEURONAL NETWORK OR ASSEMBLY Much of the research work aimed at the fundamental issues mentioned above, at the population level, has been carried out at the theoretical level. These theories are based on physiological data from small numbers of entities (neurons, synapses) and complemented by large-scale computer simulations. Most notable of these are physical theories of artificial neuronal networks.

112-115 Bhatti et al116 extended these observations to healthy vo

112-115 Bhatti et al116 extended these observations to healthy volunteers (in these subjects, a tryptophanfree drink decreased REM latency, increased

REM expressed as percentage of total sleep time, and increased REM density), findings that were only partially replicated by Voderholzer et al.117 Conclusion Polysomnographic recordings constitute a unique noninvasive tool to analyze brain function. Neurotransmission Inhibitors,research,lifescience,medical disturbances, such as those encountered in mental disorders, are reflected in alterations of sleep continuity and architecture. If we assume a neurobiological link between sleep and these disorders, the recent explosion of basic findings on the functional neuroanatomy of sleep-wake regulation and the cellular basis of the various sleep rhythms should raise new issues about our understanding of psychiatric disorders. Sleep laboratory investigations are a useful aid for the development of new psychotropic drugs, since their influence Inhibitors,research,lifescience,medical on a particular neurotransmission system could be reflected in the polysomnographic profile they induce. Moreover, this profile can be compared with the polysomnographic profiles of reference drugs. Selected Inhibitors,research,lifescience,medical abbreviations and acronyms DRN dorsal raphe nucleus GABA γ-aminobutyric acid LC locus ceruleus LDT laterodorsal tegmental (nucleus)

NP nicotine patch NREM non-rapid eye movement PTT pediculopontine tegmental (nucleus) REM rapid eye movement SCN suprachiasmatic nucleus SWS slow-wave sleep TMN tuberomammillary nucleus VLPO ventrolateral preoptic nucleus
This review focuses on information concerning antidepressants and psychotherapy in the treatment of both acute and chronic forms of unipolar Inhibitors,research,lifescience,medical depression in the English language literature. We address the use of combination therapy both from the outset of treatment and in a variety of sequences, ie, we examine the advantages of adding a targeted psychotherapy to an incompletely effective pharmacotherapy and the Inhibitors,research,lifescience,medical advantages of

adding pharmacotherapy to an incompletely effective psychotherapy. We do not address the use of these targeted psychotheraples alone, except inasmuch as to describe those targeted psychotheraples for which there is evidence of their efficacy in the treatment of various forms of unipolar depression, suggesting the potential utility of combining them with pharmacotherapy. Furthermore, although there is almost a burgeoning literature on the advantages of adding psychotherapy to pharmacotherapy in the treatment of bipolar disorder and, in particular, in the treatment of bipolar depression, the present review does not address the use of psychotherapy in the treatment of bipolar disorder. Forms of targeted psychotherapy that have been combined or sequenced with antidepressant pharmacotherapy To date, the English language literature AVL-301 mouse provides evidence for the efficacy of several forms of time-limited psychotherapy in the treatment of unipolar disorder.

For example, one report describing the use of hemodialysis for li

For example, one report describing the use of hemodialysis for lithium cardiotoxicity did not report a blood pressure or whether the patient had symptoms of end-organ dysfunction during a bradycardic episode. [22] The reader is left to guess whether the intervention reversed significant cardiotoxicity

or simply “treated a number.” Description of the intervention Case reports must include complete information about the treatments the patient received, including medication dosages and routes, Inhibitors,research,lifescience,medical important procedures and supportive and adjunctive care. In the current review, errors of omission were common. One published report described the use of warm water immersion to reverse the pain of a lionfish envenomation but failed to state the temperature of the water bath or the duration of immersion. [23] Incomplete reporting of co-interventions was also common. For example, Inhibitors,research,lifescience,medical a case report described the “successful” use of ketorolac for the treatment of chest pain from myocardial infarction. [24] The report did not state whether the patient received aspirin, Inhibitors,research,lifescience,medical beta blockers, oxygen or morphine. Description of outcomes It was common to read that a patient “stabilized within 2 hours,” “was discharged in improved condition,” “had no further symptoms” or “made a dramatic recovery.” In one case report describing the benefits of

hemodialysis for a patient who had suffered valproic acid poisoning, we learned only that “the patient’s neurologic

Inhibitors,research,lifescience,medical status promptly improved.”[25] The clinician-reader is left wondering: Which symptoms or signs improved? How completely? And for how long? In the current review, only one-third of case reports informed readers whether side effects were observed. In one case report, a telephone-assisted Heimlich maneuver was “effective” in relieving Inhibitors,research,lifescience,medical airway obstruction in a woman who had choked on a piece of meat; however, there was no mention of rib fractures, gastric injury or any other potential complication. [26] In another report, wide-complex atrial fibrillation was “effectively terminated” with ibutalide; however, there was no information about adverse effects, such as QT interval prolongation, hypotension or thromboembolism. [27] Generalizability It is the authors’ responsibility to outline important limitations to the generalizability of their case report. Edoxaban In the case of the telephone-assisted Heimlich maneuver to reverse life-threatening airway obstruction, the authors did not comment on whether the intervention would be equally safe and effective in children, obese patients, the elderly or others. One case report described the use of ultrasound to facilitate aspiration of a breast abscess. The authors wrote, “This convenient bedside Daporinad technology could make a considerable improvement in patient care,”[28] a conclusion that should be tempered by consideration of the training and experience of the ultrasonographer.

The patients were divided into two groups with 1 to 1 fashion; at

The patients were divided into two groups with 1 to 1 fashion; atorvastatin 10 mg treatment group (group I: low dose group, n = 35, 54.2 ± 12.5 years, 16 males) versus atorvastatin 40 mg treatment group (group II: high dose group, n = 35, 52.6 ± 9.8 years, 17 males). The study

protocol was approved by the Institutional GX15-070 order Review Board of our institution and informed consent was obtained from each patient. Exclusion criteria included 1) prior history of coronary intervention or myocardial infarction, 2) significant arrhythmias including atrial fibrillation, 3) combined cardiac diseases Inhibitors,research,lifescience,medical including significant valvular heart diseases or cardiomyopathy or heart failure, 4) elevated cardiac enzymes, 5) systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, 6) known hepatic Inhibitors,research,lifescience,medical dysfunction or renal insufficiency, 7) vasculitis disorders, 8) prior use of statins, 9) major life threatening illness. Measurement of FMD FMD of the brachial artery was measured according to the previously described recommendation as a non-invasive parameter of endothelial function.4)

Baseline and follow-up FMD studies were done by single well trained registered Inhibitors,research,lifescience,medical diagnostic cardiac sonographer in early morning after an overnight fasting in all patients. Baseline FMD study was done before the use of statin, and follow-up FMD study was done after the discontinuation of statin for at least 24 hours. Vasoactive substances were also discontinued

for at least 24 hours before FMD study. A 10 MHz high Inhibitors,research,lifescience,medical resolution linear vascular ultrasound transducer (Vivid 7, GE, Milwaukee, WI, USA) was used to image the brachial artery longitudinally just above the antecubital fossa. The tourniquet measuring Inhibitors,research,lifescience,medical blood pressure was placed on the forearm in order to create shear stress induced by reactive hyperemia. The diameter of the brachial artery was measured at the onset of the R-wave on electrocardiogram. After baseline measurements of the brachial artery diameter, the blood pressure cuff was inflated to at least 50 mmHg above systolic blood pressure to occlude arterial flow for 5 minutes. Subsequent deflation of the cuff induces a brief high already flow state through the brachial artery (reactive hyperemia) to accommodate the dilated resistance vessels. The resulting increase in shear stress causes the brachial artery to dilate. The brachial artery was imaged for the first 2 minutes of reactive hyperemia continuously. The flow-mediated dilatory response was used as a measure of endothelium dependent vasodilation. After the 10 minutes of rest to reestablish baseline condition, 0.6 mg of nitroglycerin was administered sublingually. The brachial artery was imaged for 5 minutes continuously to measure peak diameter. The dilatory response to nitroglycerin was used as a measure of endothelium independent vasodilation.

Docetaxel differs from paclitaxel in two positions in


Docetaxel differs from paclitaxel in two positions in

its chemical structure and this small check details alteration makes it more watersoluble. Taxanes disrupt microtubule dynamics by stabilizing the microtubule against depolymerization, enhancing their polymerization, promoting the nucleation and elongation phases of the polymerization reaction, and reducing the critical tubulin subunit concentration required Inhibitors,research,lifescience,medical for microtubule assembly. Moreover they alter the tubulin dissociation rate at both ends of the microtubule. This leads to reduced dynamic instability, whereas the association rate is not affected. After the treatment with taxanes, the microtubules Inhibitors,research,lifescience,medical are highly stable and resistant to depolymerization by cold, calcium ions, dilution, and other antimicrotubule agents. The final result is the impairment of dynamics of microtubule depolymerization, which is a critical event in the mitotic process [5]. Paclitaxel is active against primary epithelial ovarian carcinoma, breast cancer, colon, non-small-cell lung cancer, and AIDS-related Kaposi’s sarcoma in preclinical models Inhibitors,research,lifescience,medical [3, 6, 7] and is presently of common use in the treatment of several important malignancies as

lung cancer, breast cancer, Kaposi’s sarcoma, squamous cell carcinoma of the head and neck, gastric cancer, esophageal cancer, bladder cancer, and other carcinomas. Despite being clinically very active, paclitaxel and docetaxel are associated with many serious sideeffects which often preclude the prolonged use in patients. A number

of these Inhibitors,research,lifescience,medical side effects have been associated with the vehicles used for the formulation: the cremophor EL (CrEL-polyethoxylated castor oil) [8] for paclitaxel and polysorbate 80 (Tween 80) for Inhibitors,research,lifescience,medical docetaxel, respectively, that altered also their pharmacokinetic profiles; CrEL is considered to be responsible for the hypersensitivity reactions seen in patients during paclitaxel therapy. In vitro, CrEL caused L-NAME HCl axonal swelling, demyelination, and axonal degeneration, and, thus, it may also contribute to the development of neuropathy in patients receiving paclitaxel. The use of CrEL requires premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions and, despite these premedications, approximately 40% of all patients will have minor reactions (e.g., flushing and rash) and 3% will have life threatening reactions. CrEL also causes leaching of the plasticizers from polyvinyl chloride (PVC) bags and infusions sets; thus paclitaxel must be infused via the use of special non-PVC infusion systems and in-line filtration. Another effect induced by CrEL is the alteration of lipoprotein pattern and the consequent hyperlipidemia.

Yet, ironically, a significant, number of clinical trials have be

Yet, ironically, a significant, number of clinical trials have been conducted to assess the impact of a variety of pharmacological agents on cognition in normal aging, AAMI, AACD, and MCI. Many of the therapeutic approaches to AD have been utilized in such populations, less often to assess the benefits for this population than as the first step in assessing their safety and efficacy for use in AD patients. Pharmacological approaches in AACD, MCI, and normal aging Neuro transmitter deficiencies Cholinergic deficits. Numerous studies suggest that central Inhibitors,research,lifescience,medical cholinergic activity declines with age. While

profound cell loss from the cortex itself has generally not, been observed, loss of subcortical cholinergic neurons may be associated with normal aging.13 Neurons located in the subcortical basal forebrain region provide cholinergic Inhibitors,research,lifescience,medical innervation to the hippocampus and neocortex. Degeneration of these neurons likely contributes to cognitive impairment. An age-related decrease in the presynaptic activity of CAT has been reported in humans.180 CAT is considered a marker of cholinergic neurons; thus its decline

with age indicates a loss of cholinergic neurons with increasing age. Since postsynaptic muscarinic receptor binding also Inhibitors,research,lifescience,medical decreases with age,181 it appears that both presynaptic and postsynaptic cholinergic degeneration are involved Inhibitors,research,lifescience,medical in the process of normal aging. Baxter et al182 demonstrated in rodents that most of the age-related changes

in cholinergic markers were already present at ages at which behavioral impairment, was not yet maximal. A postmortem study in humans, however, somewhat, challenges this finding: cholinergic deficits, measured as activity of the cholinergic enzymes CAT and AChE, were apparent in elderly individuals with severe dementia, but not in individuals with moderate, mild, questionable, or no dementia.183 However, administration of the cholinergic antagonist scopolamine in humans has been Inhibitors,research,lifescience,medical found to impair the encoding of information into long-term memory and to impact other cognitive processes.22,184,185 Since a cholinergic antagonist, is associated with too impairments in memory and cognition, cholinergic enhancers, especially AChEIs, may ameliorate such impairments.186-188 Cholinergic enhancers (for example, arecoline, a muscarinic agonist, and choline, a precursor of ACh) have been tested on effects on performance of memory tasks in healthy volunteers after administration of the cholinergic antagonist methscopo lamine. Both drugs reversed scopolamine-induced impairment of serial learning.189 Poor baseline performers proved to be more vulnerable to both the enhancing effect, of the cholinergic agonist, and precursor and the impairment after cholinergic antagonist than good performers.

This result suggests for the first time that sleep need is under

This result suggests for the first time that sleep need is under strong genetic control, and genes can

be identified underlying sleep homeostasis. Conclusions The functions of sleep remain elusive. Understanding the regulation of sleep at the molecular level represents a powerful step to gaining access to the enigma of sleep. Although evidence has accumulated to indicate a major role for genetic factors in normal and pathological sleep, the underlying molecular mechanisms have not been elucidated, except in a few rare sleep disorders. Like most other complex traits, sleep is controlled by many genetic and environmental factors. Inhibitors,research,lifescience,medical New strategies are becoming available for genetic dissection of complex phenotypes. Inhibitors,research,lifescience,medical The hope of finding single genes that determine the presence or absence of any vigilance states in an all-or-nothing manner is highly unrealistic. However, as reviewed here, sleep-related endophenotypes, such as the sleep EEG features, can be controlled by single or major genes. A noteworthy discovery is that such genes indicate unpredicted pathways (eg, β-oxidation and vitamin A signaling) that are not only implicated in sleep but link sleep to other complex Inhibitors,research,lifescience,medical behaviors. Selected abbreviations and acronyms EEG

electroencephalogram LTP long-term potentiation NREM non-rapid eye movement QTL quantitative trait loci REM rapid eye movement SCN suprachiasmatic nucleus TPF theta peak frequency Notes This work was supported by the State of Vaud and the Swiss National Inhibitors,research,lifescience,medical Science Foundation.
Biologlcal clocks are devices that can measure time In the absence of environmental timing cues, such as GSK2656157 clinical trial changes In light Intensity, temperature, or humidity.1 The discovery of circadian clocks dates back to 1729, when the French astronomer Jean Jacques Ortous de Malran observed that mimosa plants continued to open and close their Inhibitors,research,lifescience,medical leaves in a daily manner when kept in the absence of sunlight.2 Obviously, other environmental

oscillations such as daily temperature fluctuations could have driven the cyclic leaf openings in de Mairan’s experiment, thereby challenging his conclusion about the existence of a mimosa clock. However, in 1832 the Swiss physician and botanist Augustin Pyrame de Candolle all demonstrated that in constant light mimosa plants opened and closed their leaves with a cycle of 22 hours rather than 24 hours.3 This observation provided irrefutable evidence that the leaf movement rhythm was not merely driven by cyclic environmental cues depending on the earth’s rotation, but by a self-sustained biological clock. Incidentally, “circadian” is derived from the Latin words “circa diem” and indicates that circadian clocks can measure days only approximately. Hence, the phase of circadian oscillators must be corrected daily to stay in resonance with geophysical time. The photoperiod (ie, daily variations in light intensity) is the primary Zeitgeber for the synchronization of circadian clocks.