Temporal Genomic Analysis of Homogeneous Tumor Models Reveals Key Regulators of Immune Evasion in Melanoma.

In this study, we find that Mif expression is associated with tumor growth and aggressiveness, specifically in tumors with low heterogeneity. These findings could facilitate the development of new strategies to treat patients with homogeneous, high MIF-expressing tumors that are unresponsive to immune checkpoint therapy.

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.

Subjects: One hundred eighty-three women desiring pregnancy were recruited from the local community of an academic medical center located in the Midwest and provided sleep information between February 1, 2015, and November 30, 2017.

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.

Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys.

CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor of all three pathways of the complement system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) of CSL040 were assessed in two-week intravenous (IV) bolus studies in Han Wistar rats and cynomolgus monkeys. Recovery from any effects was evaluated during a four-week recovery period.

Microfluidics to Follow Spatiotemporal Dynamics at the Nucleo-Cytoplasmic Interface During Plant Root Growth.

Nuclear dynamics refers to global/local changes in the molecular and spatial organization of genomic DNA that can occur during development or in response to environmental stress signals and eventually impact genomic functions. In plants, nuclear dynamics relies notably on the connection of the nucleus with the cytoskeleton during development. It orchestrates genomic functions in response to developmental and environmental cues.

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.

A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis.

Tissue fibrosis contributes to pathology in vital organs including the lung. Curative therapies are scant. Myofibroblasts, pivotal effector cells in tissue fibrosis, accumulate via incompletely understood interactions with their microenvironment.

cGAS Expression is Enhanced in Systemic Sclerosis Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation.

Objective: The lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The innate immune DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model.

Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).

Objectives: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor.

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.

Interventional Treatment of Pediatric Venous Thromboembolic Disease.

This review explores the clinical presentation of lower extremity DVT and pulmonary embolism (PE), treatment strategies, and outcomes for venous thromboembolism (VTE) in the pediatric population. Traditional therapy for pediatric VTE was anticoagulation alone with thrombolysis and surgery reserved only in life or limb-threatening cases. Catheter-directed thrombolysis (CDT), pharmacomechanical thrombectomy (PMT) and mechanical thrombectomy (MT) have emerged as effective and safe treatment options for VTE management.

Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts.

Introduction: The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown.

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.

Spearmint targets microtubules by (-)-carvone.

Allelopathy can provide sustainable alternatives to herbicides because it is based on specific signals rather than generic toxicity. We show that the allelopathic activity of Spearmint and Watermint is linked with their main compounds, (-)-carvone and (+)-menthofuran, both deriving from (-)-limonene. Germination of Poppy and Cress, and root growth of are inhibited by very low concentrations of (-)-carvone, acting even through the gas phase.

Proteolysis and Contractility Regulate Tissue Opening and Wound Healing by Lung Fibroblasts in 3D Microenvironments.

Damage and repair are recurring processes in tissues, with fibroblasts playing key roles by remodeling extracellular matrices (ECM) through protein synthesis, proteolysis, and cell contractility. Dysregulation of fibroblasts can lead to fibrosis and tissue damage, as seen in idiopathic pulmonary fibrosis (IPF). In advanced IPF, tissue damage manifests as honeycombing, or voids in the lungs.