This paper introduces two techniques that make the standard Quantum Approximate Optimization Algorithm (QAOA) more suitable for constrained optimization problems.
Article
Cerebrospinal Fluid Monoamine Levels in Central Disorders of Hypersomnolence
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 EcoCyc Database in 2021
The EcoCyc model-organism database collects and summarizes experimental data for Escherichia coli K-12. EcoCyc is regularly updated by the manual curation of individual database entries, such as genes, proteins, and metabolic pathways, and by the programmatic addition of results from select high-throughput analyses. Updates to the Pathway Tools software that supports EcoCyc and to the web interface that enables user access have continuously improved its usability and expanded its functionality. This article highlights recent improvements to the curated data in the areas of metabolism, transport, DNA repair, and regulation of gene expression. New and revised data analysis and visualization tools include an interactive metabolic network explorer, a circular genome viewer, and various improvements to the speed and usability of existing tools.
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.
Measuring the Impact of Trauma-Focused, Cognitive Behavioral Group Therapy with Middle School Students
This study examines differential effects of the Cognitive Behavioral Intervention for Trauma in Schools (CBITS) program on behavioral and academic outcomes of middle school students. Researchers administered screenings to grade 6 students to assess traumatic stress and then randomized those with elevated levels to the CBITS treatment ( n = 150) or comparison group ( n = 143). Analyses examined the overall impact of CBITS and differential effects among subpopulations of students who reported clinically significant externalizing ( n = 73) or internalizing behavior ( n = 181) at baseline. Results demonstrated that relative to counterparts in the comparison group, externalizers in CBITS reported significantly reduced post-traumatic stress, anxiety, anger, internalizing and externalizing problems, and total behavior problems, and they also significantly improved scores on a standardized literacy assessment at posttest. Students with internalizing behavior problems showed differential academic effects at 1-year follow-up; those in CBITS did significantly better on standardized math tests but significantly worse on a reading subtest than their counterparts.
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.
The BioCyc Metabolic Network Explorer
Background: The Metabolic Network Explorer is a new addition to the BioCyc.org website and the Pathway Tools software suite that supports the interactive exploration of metabolic networks. Any metabolic network visualization tool must by necessity show only a subset of all possible metabolite connections, or the results will be visually overwhelming. Existing tools, even those that purport to show an organism’s full meta- bolic network, limit the set of displayed connections based on predefined pathways or other preselected criteria. We sought instead to provide a tool that would give the user dynamic control over which connections to follow.
Results: The Metabolic Network Explorer is an easy-to-use, web-based software tool that allows the user to specify a starting metabolite of interest and interactively explore its immediate metabolic neighborhood in either or both directions to any desired depth, letting the user select from the full set of connected reactions. Although, as for other tools, only a small portion of the metabolic network is visible at a time, that portion is selected by the user, based on the full reaction complement, and it is easy to switch among alternate paths of interest. The display is intuitive, customizable, and provides copious links to more detailed information pages.
Conclusions: The Metabolic Network Explorer fills a gap in the set of metabolic network visualization tools and complements other modes of exploration. Its primary strengths are its ease of use, diagrams that are intuitive to biologists, and its integration with the broader corpus of data provided by a BioCyc Pathway/Genome Database.
Portable Magnetometry for Detection of Biomagnetism in Ambient Environments
This paper presents a method of optical magnetometry with parts-per-billion resolution that is able to detect biomagnetic signals generated from the human brain and heart in Earth’s ambient environment. The magnetically silent sensors measure the total magnetic field by detecting the free-precession frequency in a highly spin-polarized alkali-metal vapor. A first-order gradiometer is formed from two magnetometers that are separated by a 3-cm baseline. The gradiometer operates from a laptop consuming 5 W over a USB port, enabled by state-of-the-art microfabricated alkali-vapor cells, advanced thermal insulation, custom electronics, and compact lasers within the sensor head. The gradiometer has a sensitivity of 16 fT/cm/Hz1/2 outdoors, which we use to detect neuronal electrical currents and magnetic cardiography signals. Recording of neuronal magnetic fields is one of a few available methods for noninvasive functional brain imaging that usually requires extensive magnetic shielding and other infrastructure. This work demonstrates the possibility of a dense array of portable biomagnetic sensors that are deployable in a variety of natural environments.
