Genetic basis of human circadian rhythm disorders.

Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health

Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones.

N-Methyl-d-aspartate receptors (NMDARs) are Ca(2+)-permeable glutamate receptors that play a critical role in synaptic plasticity and promoting cell survival. However, overactive NMDARs can trigger cell death signalling pathways and have been implicated in substantia nigra pars compacta (SNc) pathology in Parkinson's disease. Calcium ion influx through NMDARs recruits Ca(2+)-dependent proteins that can regulate NMDAR activity. The surface density of NMDARs can also be regulated dynamically in response to receptor activity via Ca(2+)-independent mechanisms. We have investigated the activity-dependent regulation of NMDARs in SNc dopaminergic neurones. Repeated whole-cell agonist applications resulted in a decline in the amplitude of NMDAR currents (current run-down) that was use dependent and not readily reversible. Run-down was reduced by increasing intracellular Ca(2+) buffering or by reducing Ca(2+) influx but did not appear to be mediated by the same regulatory proteins that cause Ca(2+)-dependent run-down in hippocampal neurones. The NMDAR current run-down may be mediated in part by a Ca(2+)-independent mechanism, because intracellular dialysis with a dynamin-inhibitory peptide reduced run-down, suggesting a role for clathrin-mediated endocytosis in the regulation of the surface density of receptors. Synaptic NMDARs were also subject to current run-down during repeated low-frequency synaptic stimulation in a Ca(2+)-dependent but dynamin-independent manner. Thus, we report, for the first time, regulation of NMDARs in SNc dopaminergic neurones by changes in intracellular Ca(2+) at both synaptic and extrasynaptic sites and provide evidence for activity-dependent changes in receptor trafficking. These mechanisms may contribute to intracellular Ca(2+) homeostasis in dopaminergic neurones by limiting Ca(2+) influx through the NMDAR

Cancer Patient and clinician acceptability and feasibility of a supportive care screening and referral process

Background: Incorporating supportive care into routine cancer care is an increasing priority for the multi-disciplinary team with growing evidence of its importance to patient-centred care. How to design and deliver a process which is appropriate for patients, clinicians and health services in rural areas needs further investigation. Objective: To (i) examine the patient and clinician acceptability and feasibility of incorporating a supportive care screening and referral process into routine cancer care in a rural setting, and (ii) explore any potential influences of patient variables on the acceptability of the process. Methods: A total of 154 cancer patients and 36 cancer clinicians across two rural areas of Victoria, Australia participated. During treatment visits, patients and clinicians participated in a supportive care process involving screening, discussion of problems, and provision of information and referrals. Structured questionnaires with open and closed questions were used to measure patient and clinician acceptability and feasibility. Results: Patients and clinicians found the supportive care process highly acceptable. Screening identified relevant patient problems (90%) and problems that may not have otherwise been identified (83%). The patient-clinician discussion helped patients realize help was available (87%) and enhanced clinician-patient rapport (72%). Patients received useful referrals to services (76%). Feasibility issues included timing of screening for newly diagnosed patients, privacy in discussing problems, clinician time and availability of referral options. No patient demographic or disease factors influenced acceptability or feasibility. Conclusions: Patients and clinicians reported high acceptability for the supportive care process, although mechanisms for incorporating the process into health care need to be further developed

Quantifying phase-amplitude coupling in neuronal network oscillations

Neuroscience time series data from a range of techniques and species reveal complex, non-linear interactions between different frequencies of neuronal network oscillations within and across brain regions. Here, we briefly review the evidence that these nested, cross-frequency interactions act in concert with linearly covariant (within-frequency) activity to dynamically coordinate functionally related neuronal ensembles during behaviour. Such studies depend upon reliable quantification of cross-frequency coordination, and we compare the properties of three techniques used to measure phase-amplitude coupling (PAC)--Envelope-to-Signal Correlation (ESC), the Modulation Index (MI) and Cross-Frequency Coherence (CFC)--by standardizing their filtering algorithms and systematically assessing their robustness to noise and signal amplitude using artificial signals. Importantly, we also introduce a freely-downloadable method for estimating statistical significance of PAC, a step overlooked in the majority of published studies. We find that varying data length and noise levels leads to the three measures differentially detecting false positives or correctly identifying frequency bands of interaction; these conditions should therefore be taken into careful consideration when selecting PAC analyses. Finally, we demonstrate the utility of the three measures in quantifying PAC in local field potential data simultaneously recorded from rat hippocampus and prefrontal cortex, revealing a novel finding of prefrontal cortical theta phase modulating hippocampal gamma power. Future adaptations that allow detection of time-variant PAC should prove essential in deciphering the roles of cross-frequency coupling in mediating or reflecting nervous system function

Statistical Algorithms for Ontology-based Annotation of Scientific Literature

Background: Ontologies encode relationships within a domain in robust data structures that can be used to annotate data objects, including scientific papers, in ways that ease tasks such as search and meta-analysis. However, the annotation process requires significant time and effort when performed by humans. Text mining algorithms can facilitate this process, but they render an analysis mainly based upon keyword, synonym and semantic matching. They do not leverage information embedded in an ontology’s structure. Methods: We present a probabilistic framework that facilitates the automatic annotation of literature by indirectly modeling the restrictions among the different classes in the ontology. Our research focuses on annotating human functional neuroimaging literature within the Cognitive Paradigm Ontology (CogPO). We use an approach that combines the stochastic simplicity of naïve Bayes with the formal transparency of decision trees. Our data structure is easily modifiable to reflect changing domain knowledge. Results: We compare our results across naïve Bayes, Bayesian Decision Trees, and Constrained Decision Tree classifiers that keep a human expert in the loop, in terms of the quality measure of the F1-mirco score. Conclusions: Unlike traditional text mining algorithms, our framework can model the knowledge encoded by the dependencies in an ontology, albeit indirectly. We successfully exploit the fact that CogPO has explicitly stated restrictions, and implicit dependencies in the form of patterns in the expert curated annotations

Evaluation of Mixed-Mode Data-Link Communications for NextGen 4DT and Equivalent Visual Surface Operations

By 2025, U.S. air traffic is predicted to increase 3-fold and may strain the current air traffic management system, which may not be able to accommodate this growth. In response to this challenge, a revolutionary new concept has been proposed for U.S. aviation operations, termed the Next Generation Air Transportation System or NextGen. Many key capabilities are being identified to enable NextGen, including the use of data-link communications. Because NextGen represents a radically different approach to air traffic management and requires a dramatic shift in the tasks, roles, and responsibilities for the flight deck, there are numerous research issues and challenges that must be overcome to ensure a safe, sustainable air transportation system. Flight deck display and crew-vehicle interaction concepts are being developed that proactively investigate and overcome potential technology and safety barriers that might otherwise constrain the full realization of NextGen. The paper describes simulation research examining data-link communications during 4DT and equivalent visual surface operations