SRI Authors: Peter D Karp Abstract The Pathway Tools (PTools) software provides a suite of capabilities for storing and analyzing integrated collections of genomic and metabolic information in the form of organism-specific Pathway/Genome Databases (PGDBs). A microbial community is represented in PTools by generating a PGDB from each metagenome-assembled genome (MAG). PTools computes a metabolic […]
Biomedical sciences publications
Physiological Synchrony: A New Approach Toward Identifying Unknown Presentation Attacks on Biometric Systems
Presentation attacks are falsified biometric traits presented on biometric systems to deceive them. While biometric systems can be tuned and modified to reliably detect known presentation attacks, their performance significantly degrades when encountering unknown presentation attacks. Here, we propose a new approach toward detecting unknown presentation attacks based on the measurement and characterization of synchrony between multiple physiological signals obtained from contact and contactless sensors. Synchrony between two physiological signals was captured by analyzing the blood flow dynamics and respiration patterns. The instantaneous phase difference between two physiological signals was represented as a phase vector using the Hilbert transform and the degree of phase coherence defined as the absolute mean of phase vectors over the analysis period was used as a measure of synchrony. A weighted k-nearest neighbors classifier was then designed to detect valid and invalid biometric presentations based on the degree of phase coherence. The proposed method was validated on the detection of synchrony between two respiration patterns obtained through the measurement of chest movements using an ultra-wideband radar and respiratory sinus arrhythmia using a finger photoplethysmogram sensor on data collected from 50 individuals. It achieved a high accuracy of 95.3%, sensitivity of 96%, and specificity of 94% in detecting corrupted and nonsynchronous patterns that did not contain valid respiration signatures. The proposed method shows promise toward improving the reliability of biometric systems in the detection of unknown and sophisticated attacks that may spoof one or more of the presented biometrics.
Cerebrospinal Fluid Monoamine Levels in Central Disorders of Hypersomnolence
Study objectives: Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown.
Methods: Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness.
Results: Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity.
Conclusions: We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.
Keywords: central disorders of hypersomnolence; cerebrospinal fluid; hypersomnia; hypocretin/orexin; monoamine; narcolepsy; sleepiness.
Animal Models of Narcolepsy and the Hypocretin/orexin System: Past, Present, and Future
Animal models have advanced not only our understanding of the etiology and phenotype of the sleep disorder narcolepsy but have also informed sleep/wake regulation more generally. The identification of an inheritable narcolepsy phenotype in dogs in the 1970s allowed the establishment of a breeding colony at Stanford University, resulting in studies that provided the first insights into the genetics and neurotransmitter systems that underlie cataplexy and rapid-eye movement sleep atonia. Although the discovery of the hypocretin/orexin neuropeptides in 1998 initially seemed unrelated to sleep/wake control, the description of the phenotype of the prepro-orexin knockout (KO) mouse as strongly resembling cataplexy, the pathognomonic symptom of narcolepsy, along with identification of a mutation in hypocretin receptor-2 gene as the source of canine narcolepsy, unequivocally established the relationship between this system and narcolepsy. The subsequent discovery of hypocretin neuron degeneration in human narcolepsy demystified a disorder whose etiology had been unknown since its initial description 120 years earlier. These breakthroughs prompted the development of numerous other animal models that have allowed manipulation of the hypocretin/orexin system, thereby advancing our understanding of sleep/wake circuitry. While animal models have greatly informed understanding of this fascinating disorder and the role of the hypocretin/orexin system in sleep/wake control, the question of why these neurons degenerate in human narcolepsy is only beginning to be understood. The development of new immune-mediated narcolepsy models are likely to further inform the etiology of this sleep disorder and animal models will undoubtedly play a critical role in the development of novel narcolepsy therapeutics.
Hypocretin/Orexin Receptor Pharmacology and Sleep Phases
The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry. The broad projections of the hypocretin/orexin-producing neurons, along with differential expression of the two receptors in the projection fields of these neurons, suggest distinct roles for these receptors. While HCRTR1/OX1R is associated with regulation of motivation, reward, and autonomic functions, HCRTR2/OX2R is strongly linked to sleep-wake control. The association of hypocretin/orexin with these physiological processes has led to intense interest in the therapeutic potential of compounds targeting these receptors. Agonists and antagonists for the hypocretin/orexin receptors have shown potential for the treatment of disorders of excessive daytime somnolence and nocturnal hyperarousal, respectively, with the first antagonists approved by the US Food and Drug Administration (FDA) in 2014 and 2019 for the treatment of insomnia. These and related compounds have also been useful tools to advance hypocretin/orexin neurobiology.
Performance of Fitbit Charge 3 Against Polysomnography in Measuring Sleep in Adolescent Boys and Girls
We evaluated the performance of Fitbit Charge 3™ (FC3), a multi-sensor commercial sleep-tracker, for measuring sleep in adolescents against gold-standard laboratory polysomnography (PSG). Single-night PSG and FC3 sleep outcomes were compared in thirty-nine adolescents (22 girls; 16-19 years), 12 of whom presented with clinical/subclinical DSM-5 insomnia symptoms (7 girls). Discrepancy analysis, Bland-Altman plots, and epoch-by-epoch analyses were used to evaluate FC3 performance. The influence of several factors potentially affecting FC3 performance (e.g., sex, age, body mass index, firmware version, and magnitude of heart rate changes between consecutive PSG epochs) was also tested. In the sample of healthy adolescents, FC3 systematically underestimated PSG total sleep time by about 11 min and sleep efficiency by 2.5%, and overestimated wake after sleep onset by 9 min. Proportional biases were detected for “light” and “deep” sleep duration, resulting in significant underestimation of these parameters for those participants having longer PSG N1+ N2 and N3 durations, respectively. No significant systematic bias was detected for sleep efficiency and sleep onset latency. Epoch-by-epoch analysis showed sleep-stage sensitivity (average proportion of PSG epochs correctly classified by the device for a given sleep stage) of 68% for wake, 78% for “light” sleep, 59% for “deep” sleep, and 69% for rapid eye movement (REM) sleep in healthy sleepers. Similar results were found in the sample of adolescents with insomnia symptoms. Body mass index was positively associated with FC3-PSG discrepancies in wake after sleep onset (R 2 = .16, p = .048). The magnitude of the heart rate acceleration/deceleration between consecutive PSG epochs was an important factor affecting FC3 classifications of sleep stages. Our results are in line with a general trend in the literature, suggesting better performance for the recently introduced multi-sensor devices compared to motion-only devices, although further developments are needed to improve accuracy in sleep stage classification and wake detection. Further insight is needed to determine factors potentially affecting device performance, such as accuracy and reliability (consistency of performance over time), in different samples and conditions.
NK-Cell Biofactory as an Off-the-Shelf Cell-based Vector for Targeted In Situ Synthesis of Engineered Proteins
NK-cell Biofactory is an off-the-shelf allogeneic platform for cell-based synthesis of desired protein following recognition of a target cell while conserving the cytolytic activity. The molecular specificity of the platform can be redirected for treating a broad range of diseases.
The NK-92MI, a fast-growing cytolytic cell line with a track record of exerting clinical efficacy, is transformed into a vector for synthesizing calibrated amounts of desired engineered proteins at our disease site, that is, NK-cell Biofactory. This provides an allogeneic option to the previously published T-cell-based living vector that is limited by high manufacturing cost and product variability. The modularity of this pathway, which combines a “target” receptor with an “effector” function, enables reprogramming of the NK-cell Biofactory to target diseases with specific molecular biomarkers, such as cancer, viral infections, or auto-immune disorders, and overcome barriers that may affect the advancement of NK-cell therapies.
Physiological Responses to Acute Psychosocial Stress in Women with Menopausal Insomnia
Introduction: Insomnia disorder is a common sleep disorder and frequently emerges in the context of menopause, being associated with menopause-specific factors such as hot flashes and other psychosocial variables. Increased vulnerability to stress may also contribute to the development of insomnia in midlife women. Here, we aimed to investigate whether there are differences in physiological reactivity to acute psychosocial stress in women with menopausal insomnia compared with controls.
Methods: We investigated cortisol and heart rate [HR] responses to an acute experimental psychosocial stress (Trier Social Stress Test, TSST) approximately 1 h after waking in the morning in midlife women with ( n = 22) and without ( n = 16) DSM-IV insomnia disorder (Age: 50.05 ± 3.10 years), developed in the context of menopause.
Results: Despite similar perceived stress levels, women with insomnia showed blunted HR increases (~29% HR acceleration) to the TSST compared to controls (~44% HR acceleration) ( p = 0.026). No group differences in HR were detected at baseline or during post-task recovery. Cortisol stress responses were inconclusive, with most of the women (60%) failing to exhibit significant cortisol increases in response to the TSST. A greater magnitude of the cortisol awakening response (CAR) predicted the likelihood of being a non-responder ( p = 0.036), showing the confounding effect of CAR on cortisol stress responses.
Discussion: Women with menopausal insomnia show blunted cardiac responses to stress, suggesting alterations in the autonomic reactivity to acute stress. Whether these alterations are pre-existing or are a consequence of insomnia, needs to be determined.
Sleep and Circadian Regulation of the Autonomic Nervous System
Sleep and the autonomic nervous system (ANS) are intimately connected. The ANS is under the influence of circadian and sleep-dependent modulation. Forced desynchrony and constant routine protocols indicate strong circadian influences on heart rate (HR) and cardiac vagal activity, which fluctuate across 24 hours, with HR being lower, and vagal activity higher, during the nocturnal period. Sleep also influences ANS activity: during non-rapid-eye-movement (NREM) sleep, sympathetic activity is lower and vagal functioning is higher, compared to rapid-eye-movement (REM) sleep, where ANS activity is more similar to wakefulness. A change in ANS innervation of the heart and vasculature drives the wake-to-sleep reductions in blood pressure, HR, and systemic vascular resistance. The reduction in cardiovascular activity during sleep, prominent during NREM sleep, plays a key role in maintaining cardiovascular health, providing a “ cardiovascular holiday. ” Sleep-dependent as well as circadian regulation of vagal activity is evident very early in life and persists across adulthood. There is some evidence of sex differences in sleep-dependent vagal activity in adolescents as well as female hormone effects on nocturnal ANS measures, although further work is needed to determine the significance of these effects.
