Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.

Extended food consumption during the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain, leading to adverse health effects. Beyond the liver, how metabolic organs respond to a timed hypocaloric diet is largely unexplored. We investigated how feeding schedules impacted circadian gene expression in epididymal white and brown adipose tissue (eWAT and BAT) compared to the liver and hypothalamus.

Metabolic and chemical architecture of the mammalian circadian clock.

Circadian rhythms are endogenous periodic biological processes that occur on a daily timescale. These rhythms are generated by a transcriptional/translational feedback loop that consists of the CLOCK-BMAL1 heterodimeric transcriptional activator complex and the PER1/2-CRY1/2-CK1δ/ε repressive complex. The output pathways of this molecular feedback loop generate circadian rhythmicity in various biological processes.

DNA methylation networks underlying mammalian traits.

Using DNA methylation profiles ( = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors.

Time to target the circadian clock for drug discovery.

The circadian clock is an intracellular timekeeping device that drives daily rhythms in diverse and extensive processes throughout the body. The clock mechanism comprises a core transcription/translation negative feedback loop that is modulated by a complex set of additional interlocking feedback loops. Pharmacological manipulation of the clock may be valuable for treating many maladies including jet lag, shift work and related sleep disorders, various metabolic diseases, and cancer.

The Disordered Amino Terminus of the Circadian Enzyme Nocturnin Modulates Its NADP(H) Phosphatase Activity by Changing Protein Dynamics.

Endogenous circadian clocks control the rhythmicity of a broad range of behavioral and physiological processes, and this is entrained by the daily fluctuations in light and dark. Nocturnin () is a rhythmically expressed gene regulated by the circadian clock that belongs to the CCR4 family of endonuclease-exonuclease-phosphatase (EEP) enzymes, and the NOCT protein exhibits phosphatase activity, catalyzing the removal of the 2'-phosphate from NADP(H). In addition to its daily nighttime peak of expression, it is also induced by acute stimuli.

Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice.

Caloric restriction (CR) prolongs life span, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour feeding and 22-hour fasting, raising the question of if it is calories, fasting, or time of day that is the cause of this increased life span. We show here that 30% CR was sufficient to extend the life span by 10%; however, a daily fasting interval and circadian alignment of feeding acted together to extend life span by 35% in male C57BL/6J mice.

Natural antisense transcript of regulates the amplitude of the mouse circadian clock.

In mammals, a set of core clock genes form transcription-translation feedback loops to generate circadian oscillations. We and others recently identified a novel transcript at the () locus that is transcribed from the antisense strand of This transcript, is expressed rhythmically and antiphasic to mRNA, leading to our hypothesis that and mutually inhibit each other's expression and form a double negative feedback loop. By perturbing the expression of , we found that transcription, but not transcript, represses However, does not repress as knockdown led to a decrease in the level, indicating that forms a single negative feedback loop with and maintains the level of within the oscillatory range.

Importance of circadian timing for aging and longevity.

Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects.

Measuring problem prescription opioid use among patients receiving long-term opioid analgesic treatment: development and evaluation of an algorithm for use in EHR and claims data.

Opioid surveillance in response to the opioid epidemic will benefit from scalable, automated algorithms for identifying patients with clinically documented signs of problem prescription opioid use. Existing algorithms lack accuracy. We sought to develop a high-sensitivity, high-specificity classification algorithm based on widely available structured health data to identify patients receiving chronic extended-release/long-acting (ER/LA) therapy with evidence of problem use to support subsequent epidemiologic investigations.

Spatiotemporal regulation of NADP(H) phosphatase Nocturnin and its role in oxidative stress response.

An intimate link exists between circadian clocks and metabolism with nearly every metabolic pathway in the mammalian liver under circadian control. Circadian regulation of metabolism is largely driven by rhythmic transcriptional activation of clock-controlled genes. Among these output genes, () has one of the highest amplitude rhythms at the mRNA level.

Chemical and structural analysis of a photoactive vertebrate cryptochrome from pigeon.

Computational and biochemical studies implicate the blue-light sensor cryptochrome (CRY) as an endogenous light-dependent magnetosensor enabling migratory birds to navigate using the Earth's magnetic field. Validation of such a mechanism has been hampered by the absence of structures of vertebrate CRYs that have functional photochemistry. Here we present crystal structures of (pigeon) CRY4 that reveal evolutionarily conserved modifications to a sequence of Trp residues (Trp-triad) required for CRY photoreduction.

Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge.

Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions.

Medicine in the Fourth Dimension.

The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite.

The Circadian Protein Nocturnin Regulates Metabolic Adaptation in Brown Adipose Tissue.

Fine-tuning of transcriptional responses can be critical for long-term outcomes in response to an environmental challenge. The circadian protein Nocturnin belongs to a family of proteins that include exonucleases, endonucleases, and phosphatases and is most closely related to the CCR4 family of deadenylases that regulate the cellular transcriptome via control of poly(A) tail length of RNA transcripts. In this study, we investigate the role of Nocturnin in regulating the transcriptional response and downstream metabolic adaptations during cold exposure in brown adipose tissue.

Using natural language processing of clinical text to enhance identification of opioid-related overdoses in electronic health records data.

Purpose: To enhance automated methods for accurately identifying opioid-related overdoses and classifying types of overdose using electronic health record (EHR) databases.

Methods: We developed a natural language processing (NLP) software application to code clinical text documentation of overdose, including identification of intention for self-harm, substances involved, substance abuse, and error in medication usage. Using datasets balanced with cases of suspected overdose and records of individuals at elevated risk for overdose, we developed and validated the application using Kaiser Permanente Northwest data, then tested portability of the application using Kaiser Permanente Washington data.

Development of an algorithm to identify inpatient opioid-related overdoses and oversedation using electronic data.

Purpose: To facilitate surveillance and evaluate interventions addressing opioid-related overdoses, algorithms are needed for use in large health care databases to identify and differentiate community-occurring opioid-related overdoses from inpatient-occurring opioid-related overdose/oversedation.

Methods: Data were from Kaiser Permanente Northwest (KPNW), a large integrated health plan. We iteratively developed and evaluated an algorithm for electronically identifying inpatient overdose/oversedation in KPNW hospitals from 1 January 2008 to 31 December 2014.

Identifying and classifying opioid-related overdoses: A validation study.

Purpose: The study aims to develop and validate algorithms to identify and classify opioid overdoses using claims and other coded data, and clinical text extracted from electronic health records using natural language processing (NLP).

Methods: Primary data were derived from Kaiser Permanente Northwest (2008-2014), an integrated health care system (~n > 475 000 unique individuals per year). Data included International Classification of Diseases, Ninth Revision (ICD-9) codes for nonfatal diagnoses, International Classification of Diseases, Tenth Revision (ICD-10) codes for fatal events, clinical notes, and prescription medication records.

A novel mouse model overexpressing Nocturnin results in decreased fat mass in male mice.

Nocturnin (NOCT) belongs to the Mg dependent Exonucleases, Endonucleases, Phosphatase (EEP) family of enzymes that exhibit various functions in vitro and in vivo. NOCT is known to function as a deadenylase, cleaving poly-A tails from mRNA (messenger RNA) transcripts. Previously, we reported a role for NOCT in regulating bone marrow stromal cell differentiation through its interactions with PPARγ.

Rhythms of metabolism in adipose tissue and mitochondria.

Circadian clocks synchronize the daily functions of organisms with environmental cues like light-dark cycles and feeding rhythms. The master clock in the suprachiasmatic nucleus in the hypothalamus of the brain and the many clocks in the periphery are organized in a hierarchical manner; the master clock synchronizes the peripheral clocks, and the peripheral clocks provide feedback to the master clock in return. Not surprisingly, it has been shown that circadian rhythms and metabolism are closely linked.

Periodicity, repression, and the molecular architecture of the mammalian circadian clock.

Large molecular machines regulate daily cycles of transcriptional activity and help generate rhythmic behavior. In recent years, structural and biochemical analyses have elucidated a number of principles guiding the interactions of proteins that form the basis of circadian timing. In its simplest form, the circadian clock is composed of a transcription/translation feedback loop.

Patient perspectives on how living with a mental illness affects making and maintaining healthy lifestyle changes.

Objective: To understand the ways that mental health symptoms interfere with achieving health goals.

Methods: Individuals with mental illness diagnoses and varying levels of preventive service use were recruited from federally qualified health centers and an integrated health care delivery system and interviewed. Thematic analysis was used to characterize descriptions of how mental illness experiences influenced lifestyle change efforts.

Benefits and challenges of using service dogs for veterans with posttraumatic stress disorder.

Objective: Veterans with posttraumatic stress disorder (PTSD) are increasingly seeking service dogs to help them manage trauma-related symptoms, yet literature describing service dog use in this population is scant. The goal of this study was to document the benefits and challenges experienced by veterans with service dogs trained to assist with PTSD-related needs.

Method: Participants were veterans (N = 41) with service dogs, and their caregivers (n = 8), recruited through community-based service dog training agencies.

Perspectives on Providing And Receiving Preventive Health Care From Primary Care Providers and Their Patients With Mental Illnesses.

Purpose: Individuals with mental illnesses have higher morbidity rates and reduced life expectancy compared to the general population. Understanding how patients and providers perceive the need for prevention, as well as the barriers and beliefs that may contribute to insufficient care, are important for improving service delivery tailored to this population.

Design: Cross-sectional; mixed methods.