Circadian variation in MGMT promoter methylation and expression predicts sensitivity to Temozolomide in glioblastoma.

Purpose Recent studies show that glioblastoma (GBM) is more sensitive to Temozolomide (TMZ) in the morning. In cells, inhibiting O6-Methylguanine-DNA-Methyltransferase (MGMT) abolished time-dependent TMZ efficacy, suggesting that circadian regulation of this DNA repair enzyme underlies daily TMZ sensitivity. Here, we tested the hypotheses that MGMT-promoter methylation and protein abundance vary with time-of-day in GBM, resulting in daily rhythms in TMZ efficacy.

Uncertainty Quantification of Network Inference with Data Sufficiency.

Network inference, which involves reconstructing the connectivity structure of a network from recorded data, is essential for broadening our understanding of physical, biological, and chemical systems. Although data-driven network inference algorithms have made significant strides in recent years, determining how much data is required so that the inferred network topology faithfully mirrors the underlying network remains an essential but often overlooked subject. In this paper, we present a statistical method to determine whether the recorded data carries sufficient variability to ensure an accurate reconstruction of the true network topology.

Programmable chronogenetic gene circuits for self-regulated circadian delivery of biologic drugs.

Cells of the body rely on the circadian clock to orchestrate daily changes in physiology that impact both homeostatic and pathological conditions, such as the inflammatory autoimmune disease rheumatoid arthritis (RA). In RA, high levels of proinflammatory cytokines peak early in the morning hours, reflected by daily changes in joint stiffness. Chronotherapy (or circadian medicine) seeks to delivery drugs at optimal times to maximize their efficacy.

Tracking Daily Variations in Rest-Wake to Guide Personalized Timing of Temozolomide for High-Grade Glioma Patients.

High-grade gliomas, like glioblastoma multiforme (GBM), are the most common malignant brain tumors in adults and are treated with the chemotherapy drug temozolomide (TMZ). In humans, a retrospective analysis of patients' overall survival suggests that morning dosing may confer a benefit over evening dosing. Circadian variation in O6-methylguanine-DNA methyltransferase (MGMT) gene expression and promoter methylation has been implicated in increased tumor cell sensitivity to TMZ in the morning.

Dual-responsive synthetic gene circuit for dynamic biologic drug delivery via inflammatory and circadian signaling pathways.

Background: Engineered cells provide versatile tools for precise, tunable drug delivery, especially when synthetic stimulus-responsive gene circuits are incorporated. In many complex disease conditions, endogenous pathologic signals such as inflammation can vary dynamically over different time scales. For example, in autoimmune conditions such as rheumatoid arthritis or juvenile idiopathic arthritis, local (joint) and systemic inflammatory signals fluctuate daily, peaking in the early morning, but can also persist over long periods of time, triggering flare-ups that can last weeks to months.

Dual-responsive synthetic gene circuit for dynamic biologic drug delivery via inflammatory and circadian signaling pathways.

Background: Engineered cells provide versatile tools for precise, tunable drug delivery, especially when synthetic stimulus-responsive gene circuits are incorporated. In many complex disease conditions, endogenous pathologic signals such as inflammation can vary dynamically over different time scales. For example, in autoimmune conditions such as rheumatoid arthritis or juvenile idiopathic arthritis, local (joint) and systemic inflammatory signals fluctuate daily, peaking in the early morning, but can also persist over long periods of time, triggering flare-ups that can last weeks to months.

Programmable chronogenetic gene circuits for self-regulated circadian delivery of biologic drugs.

Cells of the body rely on the circadian clock to orchestrate daily changes in physiology that impact both homeostatic and pathological conditions, such as the inflammatory autoimmune disease rheumatoid arthritis (RA). In RA, high levels of proinflammatory cytokines peak early in the morning hours, reflected by daily changes in joint stiffness. Chronotherapy (or circadian medicine) seeks to delivery drugs at optimal times to maximize their efficacy.

A synthetic chronogenetic gene circuit for programmed circadian drug delivery.

Circadian medicine, the delivery of therapeutic interventions based on an individual's daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading to inflammatory flares, with peak disease activity in the early morning. Using a combination of synthetic biology and tissue engineering, we developed circadian-based gene circuits, termed "chronogenetics", that express a prescribed transgene downstream of the core clock gene promoter, Period2 (Per2).

Sleep variability and time to achieving pregnancy: findings from a pilot cohort study of women desiring pregnancy.

Objective: To determine whether chronodisruption is associated with achieving pregnancy.

Design: Pilot prospective cohort study.

Setting: Academic Medical Center.

The Functional Connectome Mediating Circadian Synchrony in the Suprachiasmatic Nucleus.

Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the Suprachiasmatic Nucleus (SCN). While anatomical, molecular, and genetic approaches have revealed diverse cell types and signaling mechanisms, the network wiring that enables SCN cells to communicate and synchronize remains unclear. To overcome the challenges of revealing functional connectivity from fixed tissue, we developed MITE (Mutual Information & Transfer Entropy), an information theory approach that infers directed cell-cell connections with high fidelity.

Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry.

Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock.

Organisms integrate circadian and metabolic signals to optimize substrate selection to survive starvation, yet precisely how this occurs is unclear. Here, we show that hepatocyte Period 1 (Per1) is selectively induced during fasting, and mice lacking hepatocyte Per1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. Transcriptomic analyses show failed induction of the fasting hepatokine Fgf21 in Per1-deficient mice, and single-nucleus multiome sequencing defines a putative responding hepatocyte subpopulation that fails to induce the chromatin accessibility near the Fgf21 locus.

The association between maternal sleep and circadian rhythms during pregnancy and infant sleep and socioemotional outcomes.

Studies have established that maternal sleep and circadian rhythm disturbances during pregnancy are associated with poor prenatal and perinatal outcomes for mothers and offspring. However, little work has explored its effects on infant sleep or socioemotional outcomes. The current study examined the relationship between maternal sleep and circadian rhythm disturbances during pregnancy and infant sleep and socioemotional outcomes in a diverse sample of N = 193 mothers and their infants (51% White; 52% Female; M = 11.

GABA receptor subunit composition regulates circadian rhythms in rest-wake and synchrony among cells in the suprachiasmatic nucleus.

The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) produces robust daily rhythms including rest-wake. SCN neurons synthesize and respond to γ-aminobutyric acid (GABA), but its role remains unresolved. We tested the hypothesis that γ2- and δ-subunits of the GABA receptor in the SCN differ in their regulation of synchrony among circadian cells.

Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.

Glioblastoma (GBM) is the most common primary brain tumor in adults with a poor prognosis despite aggressive therapy. A recent, retrospective clinical study found that administering Temozolomide in the morning increased patient overall survival by 6 months compared to evening. Here, we tested the hypothesis that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM.

Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma.

Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered.

Risk of pre-term birth as a function of sleep quality and obesity: prospective analysis in a large Prematurity Research Cohort.

Study Objective: To investigate whether poor sleep quality is associated with pre-term birth (PTB) risk, overall and independent of sleep apnea and habitual snoring.

Methods: We used longitudinal data from the Washington University Prematurity Research Cohort to investigate the association between poor sleep quality (defined as a Pittsburgh Sleep Quality Index > 5) and PTB, overall and independent of sleep apnea and snoring (defined by the Berlin questionnaire and prior sleep clinic attendance). Associations were investigated for sleep quality early and throughout pregnancy.

Sleep and circadian rhythms during pregnancy, social disadvantage, and alterations in brain development in neonates.

Pregnant women in poverty may be especially likely to experience sleep and circadian rhythm disturbances, which may have downstream effects on fetal neurodevelopment. However, the associations between sleep and circadian rhythm disturbances, social disadvantage during pregnancy, and neonatal brain structure remains poorly understood. The current study explored the association between maternal sleep and circadian rhythm disturbances during pregnancy and neonatal brain outcomes, examining sleep and circadian rhythm disturbances as a mediator of the effect of social disadvantage during pregnancy on infant structural brain outcomes.

The Association Between Maternal Cortisol and Infant Amygdala Volume Is Moderated by Socioeconomic Status.

Background: It has been well established that socioeconomic status is associated with mental and physical health as well as brain development, with emerging data suggesting that these relationships begin in utero. However, less is known about how prenatal socioeconomic environments interact with the gestational environment to affect neonatal brain volume.

Methods: Maternal cortisol output measured at each trimester of pregnancy and neonatal brain structure were assessed in 241 mother-infant dyads.

Deep representation learning identifies associations between physical activity and sleep patterns during pregnancy and prematurity.

Preterm birth (PTB) is the leading cause of infant mortality globally. Research has focused on developing predictive models for PTB without prioritizing cost-effective interventions. Physical activity and sleep present unique opportunities for interventions in low- and middle-income populations (LMICs).

Circadian regulation of expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma.

Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered.

Synchronization, clustering, and weak chimeras in a densely coupled transcription-based oscillator model for split circadian rhythms.

The synchronization dynamics for the circadian gene expression in the suprachiasmatic nucleus is investigated using a transcriptional circadian clock gene oscillator model. With global coupling in constant dark (DD) conditions, the model exhibits a one-cluster phase synchronized state, in dim light (dim LL), bistability between one- and two-cluster states and in bright LL, a two-cluster state. The two-cluster phase synchronized state, where some oscillator pairs synchronize in-phase, and some anti-phase, can explain the splitting of the circadian clock, i.

Kv12-encoded K+ channels drive the day-night switch in the repetitive firing rates of SCN neurons.

Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K+) channels regulate daily oscillations in the spontaneous firing rates of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K+ conductance(s) driving these daily rhythms in the repetitive firing rates of SCN neurons, however, have not been identified. To test the hypothesis that subthreshold Kv12.

Circadian Rhythms and Astrocytes: The Good, the Bad, and the Ugly.

This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity across many time domains, their cell-autonomous circadian clocks exert a particular role in controlling longer-term oscillations of brain function: the maintenance of sleep states and the circadian ordering of sleep and wakefulness. This is most evident in the central circadian pacemaker, the suprachiasmatic nucleus, where the molecular clock of astrocytes suffices to drive daily cycles of neuronal activity and behavior.

Kv12-Encoded K Channels Drive the Day-Night Switch in the Repetitive Firing Rates of SCN Neurons.

Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K ) channels regulate daily oscillations in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K conductance(s) driving these daily rhythms in repetitive firing rates, however, have not been identified. To test the hypothesis that subthreshold Kv12.