Unlike the conventional view which posits that man's activity is determined by drives that are to a degree common to all living forms not just animals, orientation theory postulates that the critical organizing force in brain function and behavior is the particular need which motile organisms have to maintain dynamic orientation in the natural environment. This not only means that sensory systems may be the key to understanding how the brain works, but also implies that man is directly responsive to geophysical forces which have a measurable impact on his function. Individual differences in aspects of sensory function are associated with different temperamental traits and varied patterns of symptom formation in mental illness. An awareness of the issues addressed by orientation theory is of importance to the interpretation of data bases containing human behavioral variables, and the development of orientation theory serves as an example of computer based research in medicine.
The synchrony of an organism with both its external and internal environment is critical to well-being and survival. As a result, organisms display daily cycles of physiology and behavior termed circadian rhythms. At the cellular level, circadian rhythms originate via interlocked autoregulatory feedback loops consisting of circadian clock genes and their proteins. These regulatory loops provide the molecular framework that enables the intracellular circadian timing system necessary to generate and maintain subsequent 24 hr rhythms. In the present study we examine the daily control of circadian clock genes and regulation of the inflammatory response by the circadian clock in the spleen.
Our results reveal that circadian clock genes as well as proinflammatory cytokines, including Tnfά and IL-1β, display rhythmic oscillations of mRNA abundance over a 24 hr cycle. LPS-induced systemic inflammation applied at midday vs. midnight reveals a differential response of proinflammatory cytokine induction in the spleen, suggesting a daily rhythm of inflammation. Exogenous melatonin administration at midday prior to LPS stimulation conveys pleiotropic effects, enhancing and repressing inflammatory cytokines, indicating melatonin functions as both a pro- and anti-inflammatory molecule in the spleen.
In summary, a daily oscillation of circadian clock genes and inflammatory cytokines as well as the ability of melatonin to function as a daily mediator of inflammation provides valuable information to aid in deciphering how the circadian timing system regulates immune function at the molecular level. However, further research is needed to clarify the precise mechanisms by which the circadian clock and melatonin have an impact upon daily immune functions in the periphery.
Hormone secretion is highly organized temporally, achieving optimal biological functioning and health. The master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the timing of circadian rhythms, including daily control of hormone secretion. In the brain, the SCN drives hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of “clock genes” that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Clock genes and proteins are also expressed in peripheral endocrine organs providing additional modes of temporal control. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways. Thus, the circadian system achieves temporal regulation of endocrine function by a combination of genetic, cellular, and neural regulatory mechanisms to ensure that each response occurs in its correct temporal niche. The availability of tools to assess the phase of molecular/cellular clocks and of powerful tract tracing methods to assess connections between “clock cells” and their targets provides an opportunity to examine circadian-controlled aspects of neurosecretion, in the search for general principles by which the endocrine system is organized.
Circadian; Diurnal; Endocrinel; Neurosecretion; Clock genes; Suprachiasmatic
Successful linguistic processing requires efficient encoding of successively-occurring auditory input in a time-constrained manner, especially under noisy conditions. In this study we examined the early neural response dynamics to rapidly-presented successive syllables in schizophrenia participants and healthy comparison subjects, and investigated the effects of noise on these responses. We used magnetoencephalography (MEG) to reveal the time-course of stimulus-locked activity over bilateral auditory cortices during discrimination of syllable pairs that differed either in voice onset time (VOT) or place of articulation (POA), in the presence or absence of noise. We also examined the association of these early neural response patterns to higher-order cognitive functions.
The M100 response, arising from auditory cortex and its immediate environs, showed less attenuation to the second syllable in patients with schizophrenia than healthy comparison subjects during VOT-based discrimination in noise. M100 response amplitudes were similar between groups for the first syllable during all three discrimination conditions, and for the second syllable during VOT-based discrimination in quiet and POA-based discrimination in noise. Across subjects, the lack of M100 attenuation to the second syllable during VOT-based discrimination in noise was associated with poorer task accuracy, lower education and IQ, and lower scores on measures of Verbal Learning and Memory and Global Cognition.
Because the neural response to the first syllable was not significantly different between groups, nor was a schizophrenia-related difference obtained in all discrimination tasks, early linguistic processing dysfunction in schizophrenia does not appear to be due to general sensory input problems. Rather, data suggest that faulty temporal integration occurs during successive syllable processing when the signal-to-noise ratio is low. Further, the neural mechanism by which the second syllable is suppressed during noise-challenged VOT discrimination appears to be important for higher-order cognition and provides a promising target for neuroscience-guided cognitive training approaches to schizophrenia.
schizophrenia; MEG; auditory processing; linguistic perception; M100; voice-onset time; place of articulation; second syllable attenuation
Time is important in clinical information systems. Representing, maintaining, querying, and reasoning about time-oriented clinical data is a major theoretical and practical research area in medical informatics. In this nonexhaustive overview, we present a brief synopsis of research efforts in designing and developing time-oriented information systems in medicine. These efforts can be viewed from either an application point of view, distinguishing between different clinical tasks (such as diagnosis versus therapy) and clinical areas (such as infectious diseases versus oncology), or a methodological point of view, distinguishing between different theoretical approaches. We also explore the two primary methodological and theoretical paths research has taken in the past decade: temporal reasoning and temporal data maintenance. Both of these research areas include efforts to model time, temporal entities, and temporal queries. Collaboration between the two areas is possible, through tasks such as the abstraction of raw time-oriented clinical data into higher-level meaningful clinical concepts and the management of different levels of temporal granularity. Such collaboration could provide a common ground and useful areas for future research and development. We conclude with our view of future research directions.
Spike timing dependent plasticity (STDP) is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a “third factor” would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic, and nicotinic receptors. Neuromodulator actions can enable STDP induction or – by increasing or decreasing the threshold – can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally based learning.
reward; learning; dopamine; acetylcholine; noradrenaline; synaptic plasticity; calcium; behavior
Loewendorf A, Benedict CA (La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA). Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything (Symposium).
Human cytomegalovirus (HCMV) (HHV-5, a β-herpesvirus) causes the vast majority of infection-related congenital birth defects, and can trigger severe disease in immune suppressed individuals. The high prevalence of societal infection, the establishment of lifelong persistence and the growing number of immune-related diseases where HCMV is touted as a potential promoter is slowly heightening public awareness to this virus. The millions of years of co-evolution between CMV and the immune system of its host provides for a unique opportunity to study immune defense strategies, and pathogen counterstrategies. Dissecting the timing of the cellular and molecular processes that regulate innate and adaptive immunity to this persistent virus has revealed a complex defense network that is shaped by CMV immune modulation, resulting in a finely tuned host–pathogen relationship.
cytokines; herpes virus; immunity; immunology; infectious disease; virology
During development, multicellular organisms must become sexually mature in order to reproduce. The developmental timing of this transition is controlled by pulses of steroid hormones, but how these pulses are generated have remained unclear? A recent paper shows that in Drosophila larvae, nucleocytoplasmic trafficking of DHR4, a nuclear receptor, in response to prothoracicotropic hormone signaling, is critical for producing the correct temporal pulses of steroid hormones that coordinate the juvenile–adult transition.
20-hydroxyecdysone; DHR4; critical weight; Cyp6t3; metamorphosis
Biological systems have powerful inbuilt mechanisms of control intended to maintain homeostasis. Cytokines are no exception to this rule, and imbalance in cytokine activities may lead to inflammation with subsequent tissue and organ damage, altered function, and death. Balance is achieved through multiple, not mutually exclusive, mechanisms including the simultaneous production of agonist and antagonistic cytokines, expression of soluble receptors or membrane-bound nonsignaling receptors, priming and/or reprogramming of signaling, and uncoupling of ligand/receptor pairing from signal transduction. Insight into cytokine balance is leading to novel therapeutic approaches particularly in autoimmune conditions, which are intimately linked to a dysregulated cytokine production.
Our sense of hearing depends on precisely organized circuits that allow us to sense, perceive, and respond to complex sounds in our environment, from music and language to simple warning signals. Auditory processing begins in the cochlea of the inner ear, where sounds are detected by sensory hair cells and then transmitted to the central nervous system by spiral ganglion neurons, which faithfully preserve the frequency, intensity, and timing of each stimulus. During the assembly of auditory circuits, spiral ganglion neurons establish precise connections that link hair cells in the cochlea to target neurons in the auditory brainstem, develop specific firing properties, and elaborate unusual synapses both in the periphery and in the CNS. Understanding how spiral ganglion neurons acquire these unique properties is a key goal in auditory neuroscience, as these neurons represent the sole input of auditory information to the brain. In addition, the best currently available treatment for many forms of deafness is the cochlear implant, which compensates for lost hair cell function by directly stimulating the auditory nerve. Historically, studies of the auditory system have lagged behind other sensory systems due to the small size and inaccessibility of the inner ear. With the advent of new molecular genetic tools, this gap is narrowing. Here, we summarize recent insights into the cellular and molecular cues that guide the development of spiral ganglion neurons, from their origin in the proneurosensory domain of the otic vesicle to the formation of specialized synapses that ensure rapid and reliable transmission of sound information from the ear to the brain.
The autonomy perspective of housework time predicts that wives’ housework time falls steadily as their earnings rise, because wives use additional financial resources to outsource or forego time in housework. We argue, however, that wives’ ability to reduce their housework varies by household task. That is, we expect that increases in wives’ earnings will allow them to forego or outsource some tasks, but not others. As a result, we hypothesize more rapid declines in wives’ housework time for low-earning wives as their earnings increase than for high-earning wives who have already stopped performing household tasks that are the easiest and cheapest to outsource or forego. Using fixed-effects models and data from the Panel Study of Income Dynamics, we find considerable support for our hypothesis. We further conclude that past evidence that wives who out-earn their husbands spend additional time in housework to compensate for their gender-deviant success in the labor market is due to the failure to account for the non-linear relationship between wives’ absolute earnings and their housework time.
household labor; autonomy; gender display; PSID
Environmental influence on developmental plasticity impacts a wide diversity of animal life from insects to humans. We now understand the epigenetic basis for many of these altered phenotypes. The five environmental factors of nutrition, behavior, stress, toxins and stochasticity work individually and in concert to affect the developing epigenome. During early embryogenesis, epigenetic marks, such as DNA methylation, are reset at specific times. Two waves of global demethylation and reestablishment of methylation frame the sensitive times for early environmental influences and will be the focus of this review. Gene transcription, translation and post-translational modification of chromatin remodeling complexes are three mechanisms affected by developmental exposure to environmental factors. To illustrate how changes in the early environment profoundly affect these mechanisms, we provide examples throughout the animal kingdom. Herein we review the history, time points and mechanisms of epigenetic gene-environment interaction.
epigenetics; development; environment; DNA methylation; plasticity; environmental epigenomics
Non-adherence to combination antiretroviral therapies (cART) is highly prevalent and significantly increases the risk of adverse HIV disease outcomes. The current study evaluated the hypothesis that prospective memory – a dissociable aspect of episodic memory describing the ability to execute a future intention – plays an important role in successful cART adherence. Seventy-nine individuals with HIV infection who were prescribed at least one antiretroviral medication underwent a comprehensive neuropsychological and neuromedical evaluation prior to completing a one-month observation of their cART adherence as measured by electronic medication monitoring. Non-adherent individuals (n = 31) demonstrated significantly poorer prospective memory functioning as compared to adherent persons (n = 48), particularly on an index of time-based ProM (i.e., elevated loss of time errors). Deficits in time-based prospective memory were independently predictive of cART non-adherence, even after considering the possible influence of established predictors of adherence, such as general cognitive impairment (e.g., retrospective learning and memory) and psychiatric comorbidity (e.g., depression). These findings extend a nascent literature showing that impairment in time-based prospective memory significantly increases the risk of medication non-adherence and therefore may guide the development of novel strategies for intervention.
Human immunodeficiency virus; AIDS dementia complex; Neuropsychological tests; Cognitive science; Patient compliance; Time perception
Adolescent aggression was explored in relation to neighborhood and genetic characteristics. Child saturation (the proportion of the population consisting of children under the age of 15), ethnic heterogeneity, poverty, and urbanicity of neighborhoods were examined in relation to adolescent aggression in 12,098 adolescents followed longitudinally for 1 year. Longitudinal analyses indicated that child saturation was positively associated with increases in aggression, with this finding emerging among those living in the same neighborhood at both testing times and those who moved between testing times. In a subsample of males for whom genetic data were available, the relation of child saturation to adolescent aggression was moderated by the monoamine oxidase A (MAOA) gene. The regression of aggression on child saturation was steeper for those with the low activity version of the MAOA allele than among those with the high activity version of the allele. The implications of the results for an understanding of the origins and ontogeny of aggression and personality disorders are discussed.
The Ziehl-Neelsen (ZN) stain is important in identifying organisms that are acid fast, principally Mycobacterium tuberculosis. However, decolorisation with a weaker acid concentration (for example 1% hydrochloric acid), often used in ZN staining in histology, can result in a wider variety of organisms appearing acid fast and can be a cause of misidentification. To illustrate this point, a patient is described with pulmonary nocardiosis who was misdiagnosed as having tuberculous empyema on pleural biopsy.
The rotation of the earth on its axis influences the physiology of all organisms. A highly conserved set of genes encoding the “core circadian regulatory proteins” (CCRP) has evolved across species. The CCRP acts through transcriptional and post-transcriptional mechanisms to direct the oscillatory expression of genes essential for key metabolic events. In addition to the light:dark cycle, the CCRP expression can be entrained by changes in feeding and physical activity patterns. While mammalian CCRP were originally associated with the central clock located within the suprachiasmatic nucleus of the brain, there is a growing body of evidence documenting the presence of the CCRP in peripheral tissues. It is now evident that the CCRP play a role in regulating the proliferation, differentiation, and function of adult stem cells in multiple organs. This concise review highlights findings concerning the role of the CCRP in modulating the adult stem cell activities. Although the manuscript focuses on hematopoietic stem cells (HSCs), bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived stem cells (ASCs) and cancer stem cells, it is likely that the contribution of the CCRP merits consideration and evaluation in all stem cell pathways.
Adipose-derived Stem Cell; Bone Marrow-derived Mesenchymal Stem Cell; Cancer Stem Cell; Circadian; Hematopoietic Stem Cell
The mechanisms that maintain the stability of chromosome ends have broad impact on genome integrity in all eukaryotes. Budding yeast is a premier organism for telomere studies. Many fundamental concepts of telomere and telomerase function were first established in yeast and then extended to other organisms. We present a comprehensive review of yeast telomere biology that covers capping, replication, recombination, and transcription. We think of it as yeast telomeres—soup to nuts.
The immune system is a host defense system comprised of both innate mechanisms able to rapidly recognize and respond to conserved pathogen associated molecular patterns (PAMPs) as well as adaptive mechanisms able to respond to a wide variety of non-conserved and conserved pathogen associated molecules. In vitro and in vivo studies have demonstrated that the kinetics and type of immune response triggered by pathogenic insults is a function of both the nature of the insult and the subsequent cross-regulatory interactions between the responding immune cells. In this context, the potential immunomodulatory influences of the nervous system have been often viewed as exerting minimal modulatory effects and thus of being largely irrelevant in the development of immune responses. Here, using a Saturday Night Live (SNL)-styled point:counterpoint format, we discuss whether and to what extent the nervous system can shape the responses of the immune system. Finally, we examine whether primary degenerative disorders of the CNS are likely to lead to alterations in immune function.
Immune privilege; TREM; CD200; VIP; PACAP; Microglia; CNS
Understanding the many facets of human reproduction has long been considered a guessing game. According to Allen Wilcox, chief of the Epidemiology Branch at the NIEHS, until now, knowing exactly when implantation of an egg into the uterine wall occurs has been impossible because the event has never been observed in humans. However, Wilcox and his team have recently taken some of the guessing out of the process by shedding light on how the timing of implantation may affect a pregnancy's outcome. The results of their research were published in the 10 June 1999 issue of the New England Journal of Medicine.
In order to examine the factors governing the timing and flexibility of skeletal muscle switching between fat and carbohydrate oxidation, Ukropcova et al. studied the effect of glucose and fatty acid availability on the preference for fat oxidation in myocytes cultured from human male quadriceps muscle taken from subjects with varied BMI, fat mass, and insulin sensitivity. The authors found that in vivo insulin sensitivity was related to a higher in vitro capacity for fat oxidation. These findings support the concept that the capacity of skeletal muscle to oxidize fat under appropriate physiological conditions is related to leanness, aerobic fitness, and insulin sensitivity.
Regulation of the repair of DNA double-strand breaks by homologous recombination is extremely important for both cell viability and the maintenance of genomic integrity. Modulation of double-strand break repair in the yeast Saccharomyces cerevisiae involves controlling the recruitment of one of the central recombination proteins, Rad52, to sites of DNA lesions. The Rad52 protein, which plays a role in strand exchange and the annealing of single strand DNA, is positively regulated upon entry into S phase, repressed during the intra-S phase checkpoint, and undergoes posttranslational modification events such as phosphorylation and sumoylation. These processes all contribute to the timing of Rad52 recruitment, its stability and function. Here, we summarize the regulatory events affecting the Rad52 protein and discuss how this regulation impacts DNA repair and cell survival.
Much remains unknown about the effect of timing and prioritization of vaccination against pandemic (pH1N1) 2009 virus on health outcomes. We adapted a city-level contact network model to study different campaigns on influenza morbidity and mortality.
We modeled different distribution strategies initiated between July and November 2009 using a compartmental epidemic model that includes age structure and transmission network dynamics. The model represents the Greater Vancouver Regional District, a major North American city and surrounding suburbs with a population of 2 million, and is parameterized using data from the British Columbia Ministry of Health, published studies, and expert opinion. Outcomes are expressed as the number of infections and deaths averted due to vaccination.
The model output was consistent with provincial surveillance data. Assuming a basic reproduction number = 1.4, an 8-week vaccination campaign initiated 2 weeks before the epidemic onset reduced morbidity and mortality by 79-91% and 80-87%, respectively, compared to no vaccination. Prioritizing children and parents for vaccination may have reduced transmission compared to actual practice, but the mortality benefit of this strategy appears highly sensitive to campaign timing. Modeling the actual late October start date resulted in modest reductions in morbidity and mortality (13-25% and 16-20%, respectively) with little variation by prioritization scheme.
Delays in vaccine production due to technological or logistical barriers may reduce potential benefits of vaccination for pandemic influenza, and these temporal effects can outweigh any additional theoretical benefits from population targeting. Careful modeling may provide decision makers with estimates of these effects before the epidemic peak to guide production goals and inform policy. Integration of real-time surveillance data with mathematical models holds the promise of enabling public health planners to optimize the community benefits from proposed interventions before the pandemic peak.
We examined associations between cognitive function (CF) and the naturally occurring daily cortisol levels using data from the Midlife in the United States survey and the National Study of Daily Experiences.
A national sample of 1,500 (mean age = 57 years; range = 33–84, 56% female) completed a phone-based battery of cognitive tasks and 3–6 months later provided saliva samples upon waking, 30 min after waking, at lunch time, and at bedtime on 4 consecutive days.
Higher CF, particularly executive function, was associated with healthier daily cortisol profiles, including a steeper diurnal cortisol slope, higher morning cortisol levels, and lower afternoon and evening cortisol levels.
The results indicate that better CF is associated with healthier profiles of naturally occurring cortisol and underscore the importance of the timing of cortisol sampling.
Cognitive function; Diurnal cortisol rhythm; Salivary cortisol
Synaptic plasticity is widely considered to be a cellular mechanism underlying learning and memory. In this issue of Neuron, Gu and Yakel show that the precise timing of a single cholinergic pulse of activity can determine whether plasticity will occur at a glutamatergic synapse and confer long-term potentiation versus depression.
Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease caused by loss of function of either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have benign tumors (hamartomas) in multiple organs though brain involvement is typically the most disabling aspect of the disease as very high rates of neurodevelopmental disorders are seen. While first described well over 120 years ago, recent advances have transformed TSC into a prototypical disorder that exemplifies the methods and potential of molecular medicine. This review will detail historical aspects of TSC and its strong associations with neurodevelopmental disorders focusing on epilepsy and autism. Finally, promising new approaches for the treatment of epilepsy and autism in patients with TSC as well as those in the general population will be discussed.
Tuber; Autism; Epilepsy; mTORC1