NTRC mediates the coupling of chloroplast redox rhythm with nuclear circadian clock in plant cells.

The intricate interplay between cellular circadian rhythms, primarily manifested in the chloroplast redox oscillations-characterized by diel hyperoxidation/reduction cycles of 2-Cys Peroxiredoxins-and the nuclear transcription/translation feedback loop (TTFL) machinery within plant cells, demonstrates a remarkable temporal coherence. However, the molecular mechanisms underlying the integration of these circadian rhythms remain elusive. Here, we elucidate that the chloroplast redox protein, NADPH-dependent thioredoxin reductase type-C (NTRC), modulates the integration of the chloroplast redox rhythms and nuclear circadian clocks by regulating intracellular levels of reactive oxygen species and sucrose.

Adolescent circadian rhythm disruption increases reward and risk-taking.

Introduction: Circadian rhythm disturbances have long been associated with the development of psychiatric disorders, including mood and substance use disorders. Adolescence is a particularly vulnerable time for the onset of psychiatric disorders and for circadian rhythm and sleep disruptions. Preclinical studies have found that circadian rhythm disruption (CRD) impacts the brain and behavior, but this research is largely focused on adult disruptions.

A translationally informed approach to vital signs for psychiatry: a preliminary proof of concept.

The nature of data obtainable from the commercial smartphone - bolstered by a translational model emphasizing the impact of social and physical zeitgebers on circadian rhythms and mood - offers the possibility of scalable and objective vital signs for major depression. Our objective was to explore associations between passively sensed behavioral smartphone data and repeatedly measured depressive symptoms to suggest which features could eventually lead towards vital signs for depression. We collected continuous behavioral data and bi-weekly depressive symptoms (PHQ-8) from 131 psychiatric outpatients with a lifetime DSM-5 diagnosis of depression and/or anxiety over a 16-week period.

EARLY FLOWERING 3 alleles affect the temperature responsiveness of the circadian clock in Chinese cabbage.

Temperature is an environmental cue that entrains the circadian clock, adapting it to local thermal and photoperiodic conditions that characterize different geographic regions. Circadian clock thermal adaptation in leafy vegetables such as Chinese cabbage (Brassica rapa ssp. pekinensis) is poorly understood but essential to sustain and increase vegetable production under changing climates.

Long-term safety and efficacy of adjunctive lacosamide in the treatment of generalized onset tonic-clonic seizures: An open-label extension trial.

Objective: This study was undertaken to assess long-term safety, tolerability, and efficacy of lacosamide (LCM) as adjunctive therapy for generalized onset tonic-clonic seizures (GTCS) in patients aged ≥4 years with idiopathic generalized epilepsy (IGE).

Methods: EP0012 (NCT02408549) was a phase 3, multicenter, open-label extension (OLE) trial. Patients were enrolled from SP0982 (NCT02408523).

Comparative transcriptomic rhythms in the mouse and human prefrontal cortex.

Alterations in multiple subregions of the human prefrontal cortex (PFC) have been heavily implicated in psychiatric diseases. Moreover, emerging evidence suggests that circadian rhythms in gene expression are present across the brain, including in the PFC, and that these rhythms are altered in disease. However, investigation into the potential circadian mechanisms underlying these diseases in animal models must contend with the fact that the human PFC is highly evolved and specialized relative to that of rodents.

Long-term efficacy, safety, and tolerability, including behavior and executive functioning, during adjunctive lacosamide treatment in pediatric patients with uncontrolled epilepsy.

Objectives: To evaluate long-term efficacy, safety, and tolerability, including behavior and executive functioning, during adjunctive lacosamide (LCM) treatment in pediatric patients (≥1 month to <18 years of age) with focal-onset or generalized seizures enrolled in 2 open-label, long-term follow-up trials.

Methods: Two open-label extension trials (SP848: NCT00938912; EP0034: NCT01964560) were conducted in pediatric patients who had participated in previous trials of adjunctive LCM (SP0847/NCT00938431; SP0966/NCT01969851; EP0060/NCT02710890; SP0967/NCT02477839; SP0969/NCT01921205); SP848 also directly enrolled eligible pediatric patients who had not previously participated in a clinical trial of LCM. Outcomes included retention, efficacy, and safety/tolerability.

Linking Mitochondrial Dysfunction, Neurotransmitter, and Neural Network Abnormalities and Mania: Elucidating Neurobiological Mechanisms of the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder.

There is growing interest in the ketogenic diet as a treatment for bipolar disorder (BD), and there are promising anecdotal and small case study reports of efficacy. However, the neurobiological mechanisms by which diet-induced ketosis might ameliorate BD symptoms remain to be determined, particularly in manic and hypomanic states-defining features of BD. Identifying these mechanisms will provide new markers to guide personalized interventions and provide targets for novel treatment developments for individuals with BD.

Disentangling transcriptomic heterogeneity within the human subgenual anterior cingulate cortex.

The subgenual anterior cingulate cortex (sgACC) is a critical site for understanding the neural correlates of affect and emotion. While the activity of the sgACC is functionally homogenous, it is comprised of multiple Brodmann Areas (BAs) that possess different cytoarchitectures. In some sgACC BAs, Layer 5 is sublaminated into L5a and L5b which has implications for its projection targets.

Molecular and cellular rhythms in excitatory and inhibitory neurons in the mouse prefrontal cortex.

Previous studies have shown that there are rhythms in gene expression in the mouse prefrontal cortex (PFC); however, the contribution of different cell types and potential variation by sex has not yet been determined. Of particular interest are excitatory pyramidal cells and inhibitory parvalbumin (PV) interneurons, as interactions between these cell types are essential for regulating the excitation/inhibition balance and controlling many of the cognitive functions regulated by the PFC. In this study, we identify cell-type specific rhythms in the translatome of PV and pyramidal cells in the mouse PFC and assess diurnal rhythms in PV cell electrophysiological properties.

Model-based multifacet clustering with high-dimensional omics applications.

High-dimensional omics data often contain intricate and multifaceted information, resulting in the coexistence of multiple plausible sample partitions based on different subsets of selected features. Conventional clustering methods typically yield only one clustering solution, limiting their capacity to fully capture all facets of cluster structures in high-dimensional data. To address this challenge, we propose a model-based multifacet clustering (MFClust) method based on a mixture of Gaussian mixture models, where the former mixture achieves facet assignment for gene features and the latter mixture determines cluster assignment of samples.

A widespread electrical brain network encodes anxiety in health and depressive states.

In rodents, anxiety is charactered by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system are fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain-state.

Molecular Rhythmicity in Glia: Importance for Brain Health and Relevance to Psychiatric Disease.

Circadian rhythms are approximate 24-hour rhythms present in nearly all aspects of human physiology, including proper brain function. These rhythms are produced at the cellular level through a transcriptional-translational feedback loop known as the molecular clock. Diurnal variation in gene expression has been demonstrated in brain tissue from multiple species, including humans, in both cortical and subcortical regions.

Cell-type and sex-specific rhythmic gene expression in the nucleus accumbens.

Circadian rhythms are critical for human health and are highly conserved across species. Disruptions in these rhythms contribute to many diseases, including psychiatric disorders. Previous results suggest that circadian genes modulate behavior through specific cell types in the nucleus accumbens (NAc), particularly dopamine D1-expressing medium spiny neurons (MSNs).

Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

Objective: Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS).

Methods: Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period.

PEDOT/CNT Flexible MEAs Reveal New Insights into the Clock Gene's Role in Dopamine Dynamics.

Substantial evidence has shown that the Circadian Locomotor Output Cycles Kaput (Clock) gene is a core transcription factor of circadian rhythms that regulates dopamine (DA) synthesis. To shed light on the mechanism of this interaction, flexible multielectrode arrays (MEAs) are developed that can measure both DA concentrations and electrophysiology chronically. The dual functionality is enabled by conducting polymer PEDOT doped with acid-functionalized carbon nanotubes (CNT).

The sleep-circadian interface: A window into mental disorders.

Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes.

Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures.

Objective: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures.

Methods: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age.

Pitfalls of using video-EEG for a trial endpoint in children aged <4 years with focal seizures.

Objective: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability.

Bipolar Disorder.

This review focuses on recent advances made towards understanding the neurobiology of bipolar disorder (BD), a chronic neuropsychiatric illness characterized by altered mood and energy states. The past few years have seen the completion of the largest genetic studies by far, which have emphasized the polygenic nature of BD as well as it's connection to other psychiatric illnesses. Furthermore, the use of inducible pluripotent stem cells has rapidly expanded.

Comparative rhythmic transcriptome profiling of human and mouse striatal subregions.

The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). In mice, this roughly corresponds to the dorsal medial striatum (DMS), dorsal lateral striatum (DLS), and ventral striatum (NAc). Each of these structures have some overlapping and distinct functions related to motor control, cognitive processing, motivation, and reward.

Thermococcus kodakarensis TK0353 is a novel AP lyase with a new fold.

Hyperthermophilic organisms thrive in extreme environments prone to high levels of DNA damage. Growth at high temperature stimulates DNA base hydrolysis resulting in apurinic/apyrimidinic (AP) sites that destabilize the genome. Organisms across all domains have evolved enzymes to recognize and repair AP sites to maintain genome stability.

Circadian rhythms and mood disorders: Time to see the light.

The importance of time is ever prevalent in our world, and disruptions to the normal light/dark and sleep/wake cycle have now become the norm rather than the exception for a large part of it. All mood disorders, including seasonal affective disorder (SAD), major depressive disorder (MDD), and bipolar disorder (BD), are strongly associated with abnormal sleep and circadian rhythms in a variety of physiological processes. Environmental disruptions to normal sleep/wake patterns, light/dark changes, and seasonal changes can precipitate episodes.

Intestinal microbial circadian rhythms drive sex differences in host immunity and metabolism.

Circadian rhythms dynamically regulate sex differences in metabolism and immunity, and circadian disruption increases the risk of metabolic disorders. We investigated the role of sex-specific intestinal microbial circadian rhythms in host metabolism using germ-free and conventionalized mice and manipulation of dietary-derived fat, fiber, and microbiota-accessible carbohydrates. Our findings demonstrate that sex differences in circadian rhythms of genes involved in immunity and metabolism depend on oscillations in microbiota, microbial metabolic functions, and microbial metabolites.